Imidazopyridine derivatives useful as inos inhibitors

ABSTRACT

The compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     in which R1, R11 and A have the meanings as given in the description are novel effective iNOS inhibitors.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel imidazopyridine derivatives, which areused in the pharmaceutical industry for the production of pharmaceuticalcompositions.

KNOWN TECHNICAL BACKGROUND

The International Application WO 03/80607 describes alkoxypyridinederivatives with inducible nitric oxide synthase (iNOS) inhibitoryactivity. The International Application WO 96/33175 contains cyclicamidino agents useful as nitric oxide synthase (NOS) inhibitors. WO2004/076451 relates to imidazo[4,5-b]quinoline derivatives and their useas NOS inhibitors. WO 02/10139 describeshexahydro-7-1H-azepin-2-yl-hexanoic acid derivatives as iNOS inhibitors.

DESCRIPTION OF THE INVENTION

It has now been found that the novel7-amino-3,4,5,6-tetrahydro-2H-azepin-2-yl-substituted imidazopyridinederivatives, which are described in greater details below, havesurprising and particularly advantageous properties.

The invention thus relates to compounds of formula I

-   in which-   A is 1-4C-alkylene or 3-7C-cycloalkylene,-   R1 is phenyl, R2- and/or R3-substituted phenyl, Har1, or R4- and/or    R5-substituted Har1,-   R11 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,-   in which-   R2 is cyano, halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy,    aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl,    1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonyl, amino, mono- or    di-1-4C-alkylamino, trifluoromethyl, hydroxyl,    1-4C-alkylsulfonylamino, phenylsulfonylamino, phenyl-1-4C-alkoxy, or    —SO₂—N(R21)R22, in which-   R21 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, phenyl-1-4C-alkyl,    Har2-1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl,    pyridyl, or R211- and/or R212-substituted phenyl, in which-   Har2 is pyridyl, thienyl, furyl or tetrahydrofuryl,-   R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono- or    di-1-4C-alkylamino,-   R212 is 1-4C-alkyl or halogen,-   R22 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl or    1-4C-alkoxy-2-4C-alkyl,-   or R21 and R22 together and with inclusion of the nitrogen atom, to    which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is a fully saturated or partially unsaturated mono- or fused    bicyclic ring or ring system made up of    -   a first constituent being a 3- to 7-membered monocyclic fully        saturated non-aromatic heterocyclic ring B,        -   which heterocyclic ring B comprises one to three heteroatoms            independently selected from nitrogen, oxygen and sulfur,        -   and which heterocyclic ring B is optionally substituted by            one or two oxo groups,    -   and, optionally, fused to said first constituent,    -   a second constituent being a benzene ring,    -   and which ring Het1 is optionally substituted by R23 on a ring        carbon atom,    -   and/or which ring Het1 is optionally substituted by R24 on a        further ring carbon atom,    -   and/or which ring Het1 is optionally substituted by an        ethylenedioxy group on a ring carbon atom,    -   and/or which ring Het1 is optionally substituted by R25 on a        ring nitrogen atom,    -   in which-   R23 is 1-4C-alkyl, 1-4C-alkoxy or phenylcarbonyl,-   R24 is 1-4C-alkyl or 1-4C-alkoxy,-   R25 is 1-4C-alkyl, phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl,    1-4C-alkoxy-2-4C-alkyl, mono- or di-1-4C-alkylamino-2-4C-alkyl,    phenyl, pyrimidyl, pyridyl, formyl, 3-7C-cycloalkyl,    3-7C-cycloalkylmethyl, or R251- and/or R252-substituted phenyl, in    which-   R251 is halogen, cyano or 1-4C-alkyl,-   R252 is halogen or 1-4C-alkyl,-   R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl, 1-4C-alkoxy,    or completely or predominantly fluorine-substituted 1-4C-alkoxy,-   Har1 is bonded to the parent molecular group via a ring carbon atom,    and is a monocyclic or fused bicyclic 5- to 10-membered unsaturated    or partially saturated heteroaryl radical comprising one to three    heteroatoms, each of which is selected from a group consisting of    nitrogen, oxygen and sulfur,-   R4 is 1-4C-alkyl, halogen, cyano, trifluoromethyl, phenyl, mono- or    di-1-4C-alkylamino, formyl, 1-4C-alkylcarbonyl, carboxyl or    1-4C-alkoxy,-   R5 is 1-4C-alkyl or halogen,-   the enantiomers, as well as the salts of these compounds and    enantiomers.

Preferably, the invention relates to compounds of formula I

-   in which-   A is 1-4C-alkylene or 3-7C-cycloalkylene,-   R1 is phenyl, R2- and/or R3-substituted phenyl, Har1, or R4- and/or    R5-substituted Har1,-   R11 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,-   in which-   R2 is cyano, halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy,    aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl,    1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonyl, amino, mono- or    di-1-4C-alkylamino, trifluoromethyl, hydroxyl,    1-4C-alkylsulfonylamino, phenylsulfonylamino, phenyl-1-4C-alkoxy, or    —SO₂—N(R21)R22, in which-   R21 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, phenyl-1-4C-alkyl,    Har2-1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl,    pyridyl, or R211- and/or R212-substituted phenyl, in which-   Har2 is pyridyl, thienyl or furyl,-   R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono- or    di-1-4C-alkylamino,-   R212 is 1-4C-alkyl or halogen,-   R22 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl or    1-4C-alkoxy-2-4C-alkyl,-   or R21 and R22 together and with inclusion of the nitrogen atom, to    which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is a fully saturated or partially unsaturated mono- or fused    bicyclic ring or ring system made up of    -   a first constituent being a 3- to 7-membered monocyclic fully        saturated non-aromatic heterocyclic ring B,        -   which heterocyclic ring B comprises one to three heteroatoms            independently selected from nitrogen, oxygen and sulfur,        -   and which heterocyclic ring B is optionally substituted by            one or two oxo groups,    -   and, optionally, fused to said first constituent,    -   a second constituent being a benzene ring,    -   and which ring Het1 is optionally substituted by R23 on a ring        carbon atom,    -   and/or which ring Het1 is optionally substituted by R24 on a        further ring carbon atom,    -   and/or which ring Het1 is optionally substituted by an        ethylenedioxy group on a ring carbon atom,    -   and/or which ring Het1 is optionally substituted by R25 on a        ring nitrogen atom,    -   in which-   R23 is 1-4C-alkyl, 1-4C-alkoxy or phenylcarbonyl,-   R24 is 1-4C-alkyl or 1-4C-alkoxy,-   R25 is 1-4C-alkyl, phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl,    1-4C-alkoxy-2-4C-alkyl, mono- or di-1-4C-alkylamino-2-4C-alkyl,    phenyl, pyrimidyl, pyridyl, formyl, 3-7C-cycloalkyl,    3-7C-cycloalkylmethyl,    -   or R251- and/or R252-substituted phenyl, in which-   R251 is halogen, cyano or 1-4C-alkyl,-   R252 is halogen or 1-4C-alkyl,-   R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl, 1-4C-alkoxy,    or completely or predominantly fluorine-substituted 1-4C-alkoxy,-   Har1 is bonded to the parent molecular group via a ring carbon atom,    and is a monocyclic or fused bicyclic 5- to 10-membered unsaturated    or partially saturated heteroaryl radical comprising one to three    heteroatoms, each of which is selected from a group consisting of    nitrogen, oxygen and sulfur,-   R4 is 1-4C-alkyl, halogen, cyano, trifluoromethyl, phenyl, mono- or    di-1-4C-alkylamino, formyl, 1-4C-alkylcarbonyl, carboxyl or    1-4C-alkoxy,-   R5 is 1-4C-alkyl or halogen,-   the enantiomers, as well as the salts of these compounds and    enantiomers.

1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl, and, particularly, the ethyl and methyl radicals.

2-4C-Alkyl is a straight-chain or branched alkyl radical having 2 to 4carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl and, particularly, ethyl radical.

1-4C-Alkylene is a straight chain alkylene radical having 1 to 4 carbonatoms. Examples which may be mentioned in this context are the methylene(—CH₂—), ethylene (—CH₂—CH₂—), trimethylene (—CH₂—CH₂—CH₂—) and thetetramethylene (—CH₂—CH₂—CH₂—CH₂—) radical.

3-7C-Cycloalkylene represents cycloalkylene radicals having 3 to 7carbon atoms. The 1,2-cyclopropylene radical is thereof preferred.

1-4C-Alkoxy is a radical which, in addition to the oxygen atom, containsa straight-chain or branched alkyl radical having 1 to 4 carbon atoms.Alkoxy radicals having 1 to 4 carbon atoms which may be mentioned inthis context are, for example, the butoxy, isobutoxy, sec-butoxy,tert-butoxy, propoxy, isopropoxy, and, particularly, the ethoxy andmethoxy radicals.

3-7C-Cycloalkyl stands for cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl andcyclopentyl are preferred.

3-7C-Cycloalkylmethyl stands for a methyl radical, which is substitutedby one of the above-mentioned 3-7C-cycloalkyl radicals. Examples whichmay be mentioned are the cyclopropylmethyl and the cyclohexylmethylradicals.

Halogen within the meaning of the present invention is iodine, bromine,or, particularly, chlorine or fluorine.

Completely or predominantly fluorine-substituted 1-4C-alkoxy is, forexample, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the1,2,2-trifluoroethoxy and in particular the 1,1,2,2-tetrafluoroethoxy,the 2,2,2-trifluoroethoxy, the trifluoromethoxy and the difluoromethoxyradical, of which the difluoromethoxy radical is preferred.“Predominantly” in this connection means that more than half of thehydrogen atoms of the 1-4C-alkoxy groups are replaced by fluorine atoms.

1-4C-Alkoxy-2-4C-alkyl stands for one of the abovementioned 2-4C-alkylradicals which is substituted by one of the abovementioned 1-4C-alkoxyradicals. Examples which may be mentioned are the 2-(methoxy)ethyl(—CH₂—CH₂—O—CH₃), the 3-(methoxy)propyl (—CH₂—CH₂—CH₂—O—CH₃), the2-(ethoxy)ethyl (—CH₂—CH₂—O—CH₂—CH₃) and the 2-(isopropoxy)ethyl(—CH₂—CH₂—O—CH—(CH₃)₂) radical.

Hydroxy-2-4C-alkyl stands for one of the abovementioned 2-4C-alkylradicals which is substituted by a hydroxyl radical. Examples which maybe mentioned are the 2-hydroxyethyl and the 3-hydroxypropyl radical.

Mono- or di-1-4C-alkylamino radicals contain in addition to the nitrogenatom, one or two of the abovementioned 1-4C-alkyl radicals. Particularlyworthy to be mentioned are the di-1-4C-alkylamino radicals, especiallythe dimethylamino, the diethylamino and the diisopropylamino radical.

Mono- or di-1-4C-alkylaminocarbonyl radicals contain in addition to thecarbonyl group one of the abovementioned mono- or di-1-4C-alkylaminoradicals. Examples which may be mentioned are the N-methyl- theN,N-dimethyl-, the N-ethyl-, the N-propyl-, the N,N-diethyl- and theN-isopropylaminocarbonyl radical.

An 1-4C-alkylcarbonylamino radical is, for example, the propionylamino[C₃H₇C(O)NH—] and the acetylamino radical [CH₃C(O)NH—].

1-4C-Alkoxycarbonyl is a carbonyl group to which one of theabovementioned 1-4C-alkoxy radicals is bonded. Examples are themethoxycarbonyl [CH₃O—C(O)—] and the ethoxycarbonyl [CH₃CH₂O—C(O)—]radical.

Phenyl-1-4C-alkoxy stands for one of the abovementioned 1-4C-alkoxyradicals, which is substituted by the phenyl radical. Examples which maybe mentioned are the benzyloxy and the phenethoxy radical.

Mono- or di-1-4C-alkylamino-2-4C-alkyl stands for one of theabovementioned 2-4C-alkyl radicals which is substituted by one of theabovementioned mono- or di-1-4C-alkylamino radicals. An example whichmay be mentioned is the 2-(dimethylamino)ethyl radical.

Phenyl-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals, which is substituted by a phenyl radical. Examples which maybe mentioned are the phenethyl and the benzyl radical.

Har2-1-4C-alkyl stands for one of the abovementioned 1-4C-alkylradicals, which is substituted by an Har2 radical. Examples which may bementioned are the 2-(Har2)-ethyl and the (Har2)-methyl radicals.

Har2 stands for pyridyl, thienyl, furyl or tetrahydrofuryl.

1-4C-Alkylcarbonyl is a carbonyl group to which one of theabovementioned 1-4C-alkyl radicals is bonded. An example is the acetyl[CH₃—C(O)—] radical.

1-4C-Alkylsulfonyl is a sulfonyl group to which one of theabovementioned 1-4C-alkyl radicals is bonded. An example is themethanesulfonyl (CH₃SO₂—) or ethanesulfonyl (CH₃CH₂SO₂—) radical.

-   Het1 refers to a fully saturated or partially unsaturated mono- or    fused bicyclic ring or ring system made up of    -   a first constituent being a 3- to 7-membered monocyclic fully        saturated non-aromatic heterocyclic ring B,        -   which heterocyclic ring B comprises one to three heteroatoms            independently selected from nitrogen, oxygen and sulfur,        -   and which heterocyclic ring B is optionally substituted by            one or two oxo groups,    -   and, optionally, fused to said first constituent,    -   a second constituent being a benzene ring,    -   and which ring Het1 is optionally substituted by R23 on a ring        carbon atom,    -   and/or which ring Het1 is optionally substituted by R24 on a        further ring carbon atom,    -   and/or which ring Het1 is optionally substituted by an        ethylenedioxy group on a ring carbon atom,    -   and/or which ring Het1 is optionally substituted by R25 on a        ring nitrogen atom.

Examples for Het1 may include, but are not limited to, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, pyrazolidinyl,imidazolidinyl, piperazinyl, homopiperazinyl, morpholinyl orthiomorpholinyl,

and the oxo substituted derivatives of the aforementioned examples suchas e.g. 2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl, 2,6-dioxopiperidinyl,2-oxopiperazinyl, 2,6-dioxopiperazinyl or 5-oxo-1,4-diazepanyl, as wellas thiomorpholine S-oxide or thiomorpholine S,S-dioxide,and the benzo-fused derivatives of the aforementioned examples such ase.g. indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl.

As used herein, the term “oxo” forms a carbonyl moiety when attached ata carbon atom, a sulfoxide moiety when attached to a sulfur atom and asulfonyl moiety when two of said terms are attached to a sulfur atom.

In one detail, Het1 is piperidinyl, pyrrolidinyl or azetidinyl, ormorpholinyl, thiomorpholinyl, S-oxo-thiomorpholinyl orS,S-dioxo-thiomorpholinyl.

In another detail, Het1 is indolinyl, isoindolinyl,1,2,3,4-tetrahydroquinolinyl or 1,2,3,4-tetrahydroisoquinolinyl.

In another detail, Het1 is substituted by R23 and/or R24 on the benzenemoiety, and is indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl.

In another detail, Het1 is piperazinyl or homopiperazinyl.

In another detail, Het1 is 4N—(R25)-piperazinyl or4N—(R25)-homopiperazinyl.

In another detail, Het1 is 2-oxopyrrolidinyl, 2-oxoimidazolidinyl,2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl,2,6-dioxopiperidinyl, 2-oxopiperazinyl, 2,6-dioxopiperazinyl or5-oxo-1,4-diazepanyl.

In another detail, Het1 is 3-(R25)-imidazolidin-2-one-yl,3-(R25)-imidazolidin-2,5-dione-yl, 4-(R25)-piperazine-2-one-yl,4-(R25)-piperazine-2,6-dione-yl or 4-(R25)-1,4-diazepan-5-one-yl.

In another detail, Het1 is substituted by R23 or by ethylenedioxy on onering carbon atom, and is piperidinyl.

In another detail, Het1 is azetidin-1-yl or 4N—(R25)-piperazin-1-yl.

Har1 refers to a monocyclic or fused bicyclic 5- to 10-memberedunsaturated or partially saturated heteroaryl radical comprising one tothree heteroatoms, each of which is selected from a group consisting ofnitrogen, oxygen and sulfur. Particularly, Har1 refers to a monocyclicor fused bicyclic 5- to 10-membered unsaturated heteroaryl(heteroaromatic) radical comprising one to three heteroatoms, each ofwhich is selected from a group consisting of nitrogen, oxygen andsulfur. More particularly, Har1 refers to a monocyclic 5- to 6-memberedor fused bicyclic 9- to 10-membered unsaturated heteroaryl(heteroaromatic) radical comprising one to three heteroatoms, each ofwhich is selected from a group consisting of nitrogen, oxygen andsulfur.

Exemplary Har1 radicals may include, without being restricted to, the5-membered derivatives furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl (precisely:1,2,4-triazolyl or 1,2,3-triazolyl), thiadiazolyl (precisely:1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl or1,2,4-thiadiazolyl) or oxadiazolyl (precisely: 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl or 1,2,4-oxadiazolyl), or the6-membered derivatives pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl;or the benzo-fused derivatives thereof, such as e.g. the 9-memberedderivatives benzothienyl, benzofuranyl, indolyl, benzoxazolyl,benzothiazolyl, indazolyl, benzimidazolyl, benzisoxazolyl,benzisothiazolyl, benzofurazanyl, benzotriazolyl, benzothiadiazolyl,isoindolyl, isofuranyl or isobenzothienyl, or the 10-memberedderivatives quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,phthalazinyl or cinnolinyl; or indolizinyl or naphthyridinyl.

It is to be noted, that the Har1 radical is bonded to the pyridine ringof the imidazopyridine scaffold via a ring carbon atom.

In one detail, as exemplary unsubstituted or R4- and/or R5-substitutedHar1 radicals may be mentioned, for example, without being restrictedthereto, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl,3-methyl-thien-2-yl, 4-methyl-thien-2-yl, 5-methyl-thien-2-yl,5-ethyl-thien-2-yl, 4-methyl-furan-2-yl, 5-methyl-furan-2-yl,5-phenyl-thien-2-yl, benzofuran-2-yl, benzothien-2-yl, benzothien-3-yl,benzoxazol-5-yl, benzthiazol-5-yl, 1-methyl-indol-5-yl, 1H-indol-2-yl,1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl,6-trifluoromethyl-indol-2-yl, 7-trifluoromethyl-indol-2-yl,5-methoxy-indol-2-yl, 1H-pyrrol-2-yl, pyrrazol-4-yl, imidazol-4-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4-methyl-pyridin-2-yl,5-methyl-pyridin-2-yl, 6-methyl-pyridin-2-yl, 5-methyl-pyridin-3-yl,2-methyl-pyridin-4-yl, 3-methyl-pyridin-4-yl, 6-methoxy-pyridin-2-yl,2-methoxy-pyridin-3-yl, 4-methoxy-pyridin-3-yl, 5-methoxy-pyridin-3-yl,6-methoxy-pyridin-3-yl, pyrimidin-5-yl, 2-methoxy-pyrimidin-5-yl,quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl,quinolin-8-yl, isoquinolin-4-yl, isoquinolin-5-yl, 5-cyano-thien-2-yl,5-carboxy-thien-2-yl, 3-carboxy-thien-2-yl, 5-dimethylamino-thien-2-yl,2-acetyl-thien-3-yl, 5-acetyl-thien-2-yl, 3,5-dimethylisoxazol-4-yl,4-chloro-thien-2-yl, 5-chloro-thien-2-yl, 3-fluoro-pyridin-4-yl,3-chloro-pyridin-4-yl, 6-fluoro-pyridin-3-yl, 6-chloro-pyridin-3-yl,2-fluoro-pyridin-3-yl, 2-chloro-pyridin-3-yl,2-chloro-3-fluoro-pyridin-4-yl, 2-chloro-5-fluoro-pyridin-3-yl,2,3-dichloro-pyridin-4-yl, 3,5-difluoro-pyridin-4-yl,2,6-dichloro-pyridin-3-yl, 2-fluoro-6-methyl-pyridin-3-yl,6-fluoro-2-methyl-pyridin-3-yl, 6-fluoro-5-methyl-pyridin-3-yl,6-chloro-5-methyl-pyridin-3-yl, 2-chloro-6-methyl-pyridin-3-yl,5,6-difluoro-indol-2-yl, or 5-chloro-indol-2-yl, as well asbenzimidazol-2-yl or 5-methyl-benzimidazol-2-yl.

In general, unless otherwise mentioned, the heterocyclic groupsmentioned herein refer to all of the possible isomeric forms thereof.

The heterocyclic groups mentioned herein refer, unless otherwise noted,in particular to all of the possible positional isomers thereof.

Thus, for example, the term pyridyl or pyridinyl includes pyridin-2-yl,pyridin-3-yl and pyridin-4-yl.

Constituents which are optionally substituted as stated herein, may besubstituted, unless otherwise noted, at any possible position.

The carbocyclic groups, alone or as part of other groups, mentionedherein may be substituted by their given substituents, unless otherwisenoted, at any substitutable ring carbon atom.

The heterocyclic groups, alone or as part of other groups, mentionedherein may be substituted by their given substituents, unless otherwisenoted, at any possible position, such as e.g. at any substitutable ringcarbon or ring nitrogen atom.

Unless otherwise noted, rings containing quaternizable imino-type ringnitrogen atoms (—N═) may be preferably not quaternized on theseimino-type ring nitrogen atoms by the mentioned substituents.

Unless otherwise noted, any heteroatom of a heterocyclic ring withunsatisfied valences mentioned herein is assumed to have the hydrogenatom(s) to satisfy the valences.

When any variable occurs more than one time in any constituent, eachdefinition is independent.

Suitable salts for compounds of the formula I—depending onsubstitution—are all acid addition salts or all salts with bases.Particular mention may be made of the pharmacologically tolerableinorganic and organic acids and bases customarily used in pharmacy.Those suitable are, on the one hand, water-insoluble and, particularly,water-soluble acid addition salts with acids such as, for example,hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonicacid, methanesulphonic acid or 3-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired—in anequimolar quantitative ratio or one differing therefrom.

On the other hand, salts with bases are—depending on substitution—alsosuitable. As examples of salts with bases are mentioned the lithium,sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium,meglumine or guanidinium salts, here, too, the bases being employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothe invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to expert's knowledge the compounds of the invention as wellas their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore all solvates and in particular all hydrates of thecompounds of formula I as well as all solvates and in particular allhydrates of the salts of the compounds of formula I.

A person skilled in the art knows on the base of his/her expertknowledge that the compounds according to this invention can exist, withregard to the fused imidazo ring, in different tautomeric forms such ase.g. in the 1-H form or, preferably, in the 3-H form, which is shown informula I. The invention includes all conceivable tautomers in pure formas well as in any mixing ratio. Particularly the present inventionincludes the pure 1-H- and, preferably, 3-H-tautomers as well as anymixtures thereof.

Additionally, a person skilled in the art knows on the base of his/herexpert knowledge that the compounds according to this invention canexist, with regard to the cyclic amidine structure in the amino-azepinering, also in different tautomeric forms such as e.g. in the exocyclicimine form or, preferably, in the exocyclic amine form, which is shownin formula I. The invention includes all conceivable tautomers in pureform as well as in any mixing ratio. Particularly the present inventionincludes the pure exocyclic imine- and, preferably, amine-tautomers aswell as any mixtures thereof.

Preferred compounds according to the present invention are thosecompounds of formula I

-   in which-   A is ethylene or cyclopropylene,-   R1 is bonded to the 6-position of the imidazopyridine scaffold, and    is phenyl, R2- and/or R3-substituted phenyl, or Har1,-   R11 is hydrogen,-   in which-   R2 is cyano, halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy,    aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl,    1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonyl, amino, mono- or    di-1-4C-alkylamino, trifluoromethyl, hydroxyl,    1-4C-alkylsulfonylamino, phenylsulfonylamino, phenyl-1-4C-alkoxy, or    —SO₂—N(R21)R22, in which-   R21 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, phenyl-1-4C-alkyl,    Har2-1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl,    pyridyl, or R211- and/or R212-substituted phenyl, in which-   Har2 is pyridyl, thienyl, furyl or tetrahydrofuryl,-   R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono- or    di-1-4C-alkylamino,-   R212 is 1-4C-alkyl or halogen,-   R22 is hydrogen, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or    1-4C-alkyl,-   or R21 and R22 together and with inclusion of the nitrogen atom, to    which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl,    thiomorpholinyl, S-oxo-thiomorpholinyl or S,S-dioxo-thiomorpholinyl,    or    -   indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl or        1,2,3,4-tetrahydroisoquinolinyl, or piperazinyl or        homopiperazinyl, or    -   4N—(R25)-piperazinyl or 4N—(R25)-homopiperazinyl,    -   2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl,        2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl,        2,6-dioxopiperidinyl, 2-oxopiperazinyl, 2,6-dioxopiperazinyl or        5-oxo-1,4-diazepanyl,    -   3-(R25)-imidazolidin-2-one-yl,        3-(R25)-imidazolidin-2,5-dione-yl, 4-(R25)-piperazine-2-one-yl,    -   4-(R25)-piperazine-2,6-dione-yl or        4-(R25)-1,4-diazepan-5-one-yl, in which-   R25 is 1-4C-alkyl, phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl,    1-4C-alkoxy-2-4C-alkyl, mono- or di-1-4C-alkylamino-2-4C-alkyl,    phenyl, pyrimidyl, pyridyl, formyl, 3-7C-cycloalkyl,    3-7C-cycloalkylmethyl, or R251- and/or R252-substituted phenyl, in    which-   R251 is halogen, cyano or 1-4C-alkyl,-   R252 is halogen or 1-4C-alkyl,-   R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl, 1-4C-alkoxy,    or completely or predominantly fluorine-substituted 1-4C-alkoxy,-   Har1 is bonded to the parent molecular group via a ring carbon atom,    and is pyridyl, thienyl, furanyl indolyl, benzothienyl,    benzofuranyl, benzoxazolyl, benzothiazolyl, quinolyl or isoquinolyl,-   the enantiomers, as well as the salts of these compounds and    enantiomers.

Further preferred compounds according to the present invention are thosecompounds of formula I in which

-   A is ethylene or cyclopropylene,-   R1 is bonded to the 6-position of the imidazopyridine scaffold, and    is phenyl, R2- and/or R3-substituted phenyl, or Hart-   R11 is hydrogen,-   in which-   R2 is cyano, halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy,    aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl,    1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonyl, amino, mono- or    di-1-4C-alkylamino, trifluoromethyl, hydroxyl,    1-4C-alkylsulfonylamino, phenylsulfonylamino, phenyl-1-4C-alkoxy, or    —SO₂—N(R21)R22, in which-   R21 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, phenyl-1-4C-alkyl,    Har2-1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl,    pyridyl, or R211- and/or R212-substituted phenyl, in which-   Har2 is pyridyl, thienyl or furyl,-   R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono- or    di-1-4C-alkylamino,-   R212 is 1-4C-alkyl or halogen,-   R22 is hydrogen, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or    1-4C-alkyl,-   or R21 and R22 together and with inclusion of the nitrogen atom, to    which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl,    thiomorpholinyl, S-oxo-thiomorpholinyl or S,S-dioxo-thiomorpholinyl,    or    -   indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl or        1,2,3,4-tetrahydroisoquinolinyl, or piperazinyl or        homopiperazinyl, or    -   4N—(R25)-piperazinyl or 4N—(R25)-homopiperazinyl,    -   2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl,        2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl,        2,6-dioxopiperidinyl, 2-oxopiperazinyl, 2,6-dioxopiperazinyl or        5-oxo-1,4-diazepanyl,    -   3-(R25)-imidazolidin-2-one-yl,        3-(R25)-imidazolidin-2,5-dione-yl, 4-(R25)-piperazine-2-one-yl,    -   4-(R25)-piperazine-2,6-dione-yl or        4-(R25)-1,4-diazepan-5-one-yl, in which-   R25 is 1-4C-alkyl, phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl,    1-4C-alkoxy-2-4C-alkyl, mono- or di-1-4C-alkylamino-2-4C-alkyl,    phenyl, pyrimidyl, pyridyl, formyl, 3-7C-cycloalkyl,    3-7C-cycloalkylmethyl,    -   or R251- and/or R252-substituted phenyl, in which R251 is        halogen, cyano or 1-4C-alkyl,-   R252 is halogen or 1-4C-alkyl,-   R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl, 1-4C-alkoxy,    or completely or predominantly fluorine-substituted 1-4C-alkoxy,-   Har1 is bonded to the parent molecular group via a ring carbon atom,    and is pyridyl, thienyl, furanyl indolyl, benzothienyl,    benzofuranyl, benzoxazolyl, benzothiazolyl, quinolyl or isoquinolyl,-   the enantiomers, as well as the salts of these compounds and    enantiomers.

Further preferred compounds according to the present invention are thosecompounds of formula I in which

-   A is ethylene,-   R1 is bonded to the 6-position of the imidazopyridine scaffold, and    is phenyl, or R2- and/or R3-substituted phenyl,-   R11 is hydrogen,-   in which-   R2 is cyano, halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy,    aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl,    1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonyl, amino, mono- or    di-1-4C-alkylamino, trifluoromethyl, hydroxyl,    1-4C-alkylsulfonylamino, phenylsulfonylamino, or phenyl-1-4C-alkoxy,-   R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl, 1-4C-alkoxy,    or completely or predominantly fluorine-substituted 1-4C-alkoxy,-   the enantiomers, as well as the salts of these compounds and    enantiomers.

Further preferred compounds according to the present invention are thosecompounds of formula I

-   in which-   A is ethylene,-   R1 is bonded to the 6-position of the imidazopyridine scaffold, and    is R2- and/or R3-substituted phenyl,-   R11 is hydrogen,-   in which-   R2 is —SO₂—N(R21)R22, in which R21 is hydrogen, 1-4C-alkyl,    3-7C-cycloalkyl, phenyl-1-4C-alkyl, Har2-1-4C-alkyl,    hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl, pyridyl, or    R211- and/or R212-substituted phenyl, in which Har2 is pyridyl,    thienyl or furyl,-   R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono- or    di-1-4C-alkylamino,-   R212 is 1-4C-alkyl or halogen,-   R22 is hydrogen, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or    1-4C-alkyl,-   or R21 and R22 together and with inclusion of the nitrogen atom, to    which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl,    thiomorpholinyl, S-oxo-thiomorpholinyl or S,S-dioxo-thiomorpholinyl,    or    -   indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl or        1,2,3,4-tetrahydroisoquinolinyl, or piperazinyl or        homopiperazinyl, or    -   4N—(R25)-piperazinyl or 4N—(R25)-homopiperazinyl,    -   2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl,        2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl,        2,6-dioxopiperidinyl, 2-oxopiperazinyl, 2,6-dioxopiperazinyl or        5-oxo-1,4-diazepanyl,    -   3-(R25)-imidazolidin-2-one-yl,        3-(R25)-imidazolidin-2,5-dione-yl, 4-(R25)-piperazine-2-one-yl,    -   4-(R25)-piperazine-2,6-dione-yl or        4-(R25)-1,4-diazepan-5-one-yl, in which-   R25 is 1-4C-alkyl, phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl,    1-4C-alkoxy-2-4C-alkyl, mono- or di-1-4C-alkylamino-2-4C-alkyl,    phenyl, pyrimidyl, pyridyl, formyl, 3-7C-cycloalkyl,    3-7C-cycloalkylmethyl, or R251- and/or R252-substituted phenyl, in    which-   R251 is halogen, cyano or 1-4C-alkyl,-   R252 is halogen or 1-4C-alkyl,-   R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl, 1-4C-alkoxy,    or completely or predominantly fluorine-substituted 1-4C-alkoxy,-   the enantiomers, as well as the salts of these compounds and    enantiomers.

Further preferred compounds according to the present invention are thosecompounds of formula I in which

-   A is ethylene,-   R1 is bonded to the 6-position of the imidazopyridine scaffold, and    is Har1,-   R11 is hydrogen,-   in which-   Har1 is bonded to the parent molecular group via a ring carbon atom,    and is pyridyl, thienyl, furanyl, indolyl, benzothienyl,    benzofuranyl, benzoxazolyl, benzothiazolyl, quinolyl or isoquinolyl,    the enantiomers, as well as the salts of these compounds and    enantiomers.

Further preferred compounds according to the present invention are thosecompounds of formula I in which

-   A is 1-4C-alkylene,-   R1 is phenyl, R2-substituted phenyl or Har1,-   R11 is hydrogen,-   in which-   R2 is cyano, 1-4C-alkoxy or —SO₂—N(R21)R22, in which-   R21 is hydrogen, 1-4C-alkyl, Har2-1-4C-alkyl, phenyl or R211- and/or    R212-substituted phenyl, in which-   Har2 is furyl or tetrahydrofuryl,-   R211 is 1-4C-alkyl or halogen,-   R212 is 1-4C-alkyl or halogen,-   R22 is hydrogen or 1-4C-alkyl,-   or R21 and R22 together and with inclusion of the nitrogen atom, to    which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is a 3- to 7-membered monocyclic fully saturated non-aromatic    heterocyclic ring B, which heterocyclic ring B comprises one to    three heteroatoms independently selected from nitrogen, oxygen and    sulfur,    -   and which ring Het1 is optionally substituted by R23 on a ring        carbon atom,    -   and/or which ring Het1 is optionally substituted by R25 on a        ring nitrogen atom, in which-   R23 is 1-4C-alkyl,-   R25 is 1-4C-alkyl,-   Har1 is bonded to the parent molecular group via a ring carbon atom,    and is a monocyclic or fused bicyclic 5- to 10-membered unsaturated    heteroaryl radical comprising one to three heteroatoms, each of    which is selected from a group consisting of nitrogen, oxygen and    sulfur,-   the enantiomers, as well as the salts of these compounds and    enantiomers.

Further preferred compounds according to the present invention are thosecompounds of formula I in which

-   A is ethylene,-   R1 is phenyl, R2-substituted phenyl or Har1,-   R11 is hydrogen,-   in which-   R2 is cyano, 1-4C-alkoxy or —SO₂—N(R21)R22, in which-   R21 is hydrogen, 1-4C-alkyl, Har2-1-4C-alkyl or R211- and/or    R212-substituted phenyl, in which-   Har2 is tetrahydrofuryl,-   R211 is 1-4C-alkyl or halogen,-   R212 is 1-4C-alkyl,-   R22 is hydrogen or 1-4C-alkyl,-   or R21 and R22 together and with inclusion of the nitrogen atom, to    which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is a 4- to 6-membered monocyclic fully saturated non-aromatic    heterocyclic ring B, which heterocyclic ring B comprises one to    three nitrogen atoms, and which ring Het1 is optionally substituted    by R25 on a ring nitrogen atom, in which-   R25 is 1-4C-alkyl,-   Har1 is bonded to the parent molecular group via a ring carbon atom,    and is a fused bicyclic 9-membered unsaturated heteroaryl radical    comprising one oxygen atom,-   the enantiomers, as well as the salts of these compounds and    enantiomers.

Further preferred compounds according to the present invention are thosecompounds of formula I

-   in which-   A is ethylene,-   R1 is phenyl, R2-substituted phenyl or Har1,-   R11 is hydrogen,-   in which-   R2 is cyano, 1-4C-alkoxy or —SO₂—N(R21)R22, in which-   R21 is hydrogen, 1-4C-alkyl, Har2-1-4C-alkyl or R211- and/or    R212-substituted phenyl, in which-   Har2 is tetrahydrofuryl,-   R211 is 1-4C-alkyl or halogen,-   R212 is 1-4C-alkyl,-   R22 is hydrogen or 1-4C-alkyl,-   or R21 and R22 together and with inclusion of the nitrogen atom, to    which they are bonded, form a heterocyclic ring Het1, in which-   Het1 is an azetidinyl or piperazinyl ring, which ring Het1 is    optionally substituted by R25 on a ring nitrogen atom, in which-   R25 is 1-4C-alkyl,-   Har1 is bonded to the parent molecular group via a ring carbon atom,    and is a benzofuranyl ring,-   the enantiomers, as well as the salts of these compounds and    enantiomers.

A special interest in the compounds according to the present inventionrefers to those compounds of this invention which are included—withinthe scope of this invention—by one or, when possible, a combination ofmore of the following embodiments:

One embodiment of the compounds of the present invention includes thosecompounds of formula I in which A is ethylene.

Another embodiment of the compounds of the present invention includesthose compounds of formula I in which R11 is hydrogen.

Another special embodiment of the compounds of the present inventionincludes those compounds of formula I in which A is ethylene and R11 ishydrogen.

Another embodiment of the compounds of the present invention includesthose compounds of formula I in which R1 is phenyl and A is ethylene andR11 is hydrogen.

Another embodiment of the compounds of the present invention includesthose compounds of formula I in which R1 is R2— and/or R3-substitutedphenyl and A is ethylene and R11 is hydrogen.

Another embodiment of the compounds of the present invention includesthose compounds of formula I in which R1 is R2-substituted phenyl and Ais ethylene and R11 is hydrogen.

Another embodiment of the compounds of the present invention includesthose compounds of formula I in which R1 is Har1 and A is ethylene andR11 is hydrogen.

Another embodiment of the compounds of the present invention includesthose compounds of formula I in which R1 is R4- and/or R5-substitutedHar1 and A is ethylene and R11 is hydrogen.

Another embodiment of the compounds of the present invention includesthose compounds of formula I in which R1 is bonded to the 6-position ofthe imidazopyridine ring system.

The substituents R2 and R3 of compounds according to this invention canbe attached in the ortho, meta or para position with respect to thebinding position in which the phenyl ring is bonded to theimidazopyridine ring system, whereby a special embodiment of thecompounds of the present invention include those compounds of formula Iin which R2 is attached in the meta or, particularly, para position.

In this context, another embodiment of the compounds of the presentinvention include those compounds of formula I in which R3 is attachedin the ortho or meta position and R2 is attached in the para positionwith respect to the binding position in which the phenyl ring is bondedto the imidazopyridine ring system.

The compounds of formula I are chiral compounds having a chiral centerin the binding position of the amino-azepinyl ring to the moiety A.

The invention includes all conceivable stereoisomers in pure form aswell as in any mixing ratio including the racemates. In particular, thechiral center may have the absolute configuration R or the absoluteconfiguration S (according to the rules of Cahn, Ingold and Prelog). A“pure stereoisomer” is to be understood as containing not more than 5 wt% of the other stereoisomer, preferably not more than 3 wt % and morepreferably not more than 1 wt % of other stereoisomer.

The enantiomers can be separated in a manner known per se (for exampleby preparation and separation of appropriate diastereoisomericcompounds). Enantiomerically pure starting compounds or enantiomericallypure final compounds can be prepared via asymmetric syntheses; or bymeans of salt formation of the racemic compounds with optically activeacids or bases, subsequent resolution of the salts and release of thedesired compound from the salt. Enantiomerically pure starting compoundsas well as enantiomerically pure compounds of the formula I can be alsoobtained from the racemates by chromatographic separation on chiralseparating columns; by derivatization with chiral auxiliary reagents,subsequent diastereomer separation and removal of the chiral auxiliarygroup; or by (fractional) crystallization from a suitable solvent.

Compounds of formula I can be obtained as outlined in the followingreaction schemes and described below or as specified by way of examplein the following examples or similarly or analogously thereto.

In the following reaction schemes the synthesis of compounds of formulaI, in which A is ethylene, is exemplarily described.

Thus, as shown in reaction scheme 1 below, compounds of formula IV, inwhich R11 has the meanings given above and X is a suitable leavinggroup, particularly iodine or, especially, bromine, is reacted withboronic acids or, particularly, boronic acid esters (e.g. pinacolesters) of formula Y—R1, in which R1 has the meanings given above and Yis a boronic acid group or, particularly, a boronic acid ester group,suitably a cyclic boronic acid ester group such as, for example, theboronic acid pinacol ester group, under conditions appropriate for aSuzuki reaction to occur to give corresponding compounds of formula III.

The Suzuki reaction can be carried out in a manner as described in thefollowing examples or as known to the person skilled in the art inorganic solvents alone, for example in toluene, benzene,dimethylformamide or in ethereal (e.g. dimethoxyethane or, inparticular, dioxane) or alcohol solvents or in a mixture thereof, orpreferably in a mixture comprising an organic solvent (in particulardioxane) and water, with organic (e.g. triethylamine) or preferablyinorganic base (e.g. potassium hydroxide, thallium hydroxide, sodiumbicarbonate, cesium carbonate, cesium fluoride or, in particular,potassium carbonate or sodium carbonate) in the presence of a transitionmetal catalyst, for example, a nickel or, in particular, palladiumcatalyst (e.g. Pd(OAc)₂, PdCl₂(PPh₃)₂ or Pd(PPh₃)₄, in particular,PdCl₂(PCy₃)₂ or PdCl₂(dppf), Ac=acetyl, Ph=phenyl, Cy=cyclohexyl,dppf=1,1′-bis(diphenylphosphino)-ferrocene), and, optionally, lithiumchloride, suitably at elevated temperature.

Boronic acids or boronic acid esters (e.g. pinacol esters) of formulaR1-Y, in which R1 and Y have the meanings given above, are known or canbe obtained in an art-known manner or analogously or similarly to knowncompounds. Boronic acid esters (e.g. pinacol esters) of formula R1-Y canbe prepared, for example, starting from the corresponding triflates or,particularly, halides, preferably the bromides or iodides, which areart-known or which can be obtained according to art-known procedures,using e.g. bis-(pinacolato)-diboron in the presence of a transitionmetal, preferably palladium, catalyst. Optionally the boronic acidesters obtained can be isolated or, preferably, they are generated insitu and used in the subsequent Suzuki reaction without isolation.

The cyclic amide structure of compounds of formula III is converted intothe cyclic amidine structure of compounds of formula I in a manner knownto the person skilled in the art or as described in the followingexamples, e.g. via the thioamide structure of compounds of formula II(obtainable under suitable conditions with the aid of Lawesson'sreagent) which is aminated with ammonia to give compounds of formula I.

Compounds of formula IV, in which R11 and X have the meanings givenabove, are obtained as shown in reaction scheme 2.

In a Wittig reaction, compounds of formula VI, in which X and R11 havethe meanings given above, are reacted with compounds of formula VII togive corresponding compounds of formula V. With regard to theconfiguration of the exocyclic double bond obtained by Wittig reaction,the outcome can be a Z- or, particularly, E-configurated product or,especially, a mixture thereof. Said reaction can be carried out in amanner as described in the following examples or as known to the personskilled in the art according to a Wittig reaction, in a suitable solventsuch as, for example, methanol, tetrahydrofurane, toluene or a mixturethereof, using a suitable base such as, for example, sodium hydride orsodium methanolate, at room temperature or at elevated temperature.

The reduction of the abovementioned exocyclic double bond following thedeprotection reaction leads to desired compounds of formula IV, in whichX and R11 have the meanings given above. This reaction can be carriedout as hydrogenation reaction according to procedures known to theperson skilled in the art or according to the following examples in thepresence of a suitable catalyst, such as, for example, palladium onactive carbon or platinum dioxide, in a suitable solvent (e.g. in alower alcohol, such as, for example, methanol). If necessary, acid, suchas trifluoracetic acid or acetic acid, can be added to the solvent.

Compounds of formula VI are obtained as shown in reaction scheme 3. In afirst reaction step of reaction scheme 3, diamino compounds of formulaX, in which X and R11 have the meanings indicated above, are convertedinto 3H-imidazo[4,5-b]pyridine derivatives in a manner known from theliterature or with analogous or similar use of processes known from theliterature. For example, said compounds of formula X can be reacted withcarboxylic acids or carboxylic acid derivatives of formula Z1-CH₂—Z2, inwhich Z1 is a suitable leaving group, advantageously chlorine, and Z2 isa carboxyl or, particularly, cyano radical, to give in a condensationreaction compounds of formula IX, in which R1, X and Z1 have themeanings mentioned above. This condensation reaction can be carried outas known to one of ordinary skill in the art or as described by way ofexample in the following examples, for example, by using a suitablecondensing agent such as preferably polyphosphoric acid in a suitableinert solvent or, preferably, without further solvent using an excess ofcondensing agent, preferably at elevated temperature.

As shown in reaction scheme 3, compounds of formula IX can be convertedwith certain phosphanes into corresponding phosphonium salts which canbe used in the abovementioned Wittig reaction. Preferably, compounds offormula IX are reacted with triphenylphosphane (R=phenyl) or,particularly, tributylphosphane (R=butyl) to give correspondingcompounds of formula VI. Said reaction can be carried out in a mannerhabitual per se or as described in the following examples in a suitablesolvent such as, for example, acetonitrile or N,N-dimethylformamide or amixture thereof, at elevated temperature, optionally in the presence ofan auxiliary such as tetrabutylammonium iodide.

Compounds of formula X are known or can be obtained according to knownprocedures (see e.g. S.-X. Cai et al., J. Med. Chem. 1997, 40(22),3679-3686).

Compounds of formula VII are obtained as shown in reaction scheme 2 or 4by oxidation of compounds of formula XI or VIII, respectively.Optionally compounds of formula VII obtained can be isolated or,preferably, they are generated in situ and used in the subsequent Wittigreaction without isolation.

Compounds of formula XI can be obtained as outlined in reaction scheme 4according to known procedures (see e.g. L. Benati et al., J. Org. Chem.1999, 64(21), 7836-7841 and L. Benati et al., J. Org. Chem. 1999,64(14), 5132-5138) or as described in the following examples via amodified Schmidt rearrangement and subsequent reduction of the estergroup.

Optionally, compounds of formula I can be converted into their salts,or, optionally, salts of the compounds of formula I can be convertedinto the free compounds. Corresponding processes are known to the personskilled in the art.

It is known to the person skilled in the art that if there are a numberof reactive centers on a starting or intermediate compound it may benecessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in T. W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999,3^(rd) Ed, or in P. Kocienski, Protecting Groups, Thieme MedicalPublishers, 2000.

The substances according to the invention are isolated and purified in amanner known per se, e.g. by distilling off the solvent in vacuo andrecrystallizing the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such ascolumn chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent(for example a ketone like acetone, methylethylketone, ormethylisobutylketone, an ether, like diethyl ether, tetrahydrofuran ordioxane, a chlorinated hydrocarbon, such as methylene chloride orchloroform, or a low molecular weight aliphatic alcohol, such asethanol, isopropanol) which contains the desired acid, or to which thedesired acid is then added. The salts are obtained by filtering,reprecipitating, precipitating with a non-solvent for the addition saltor by evaporating the solvent. Salts obtained can be converted bybasification into the free compounds which, in turn, can be convertedinto salts. In this manner, pharmacologically non-tolerable salts can beconverted into pharmacologically tolerable salts.

Suitably, the conversions mentioned in this invention can be carried outanalogously or similarly to methods which are familiar per se to theperson skilled in the art, for example, in the manner which is describedby way of example in the following examples.

The person skilled in the art knows on the basis of his/her knowledgeand on the basis of those synthesis routes, which are shown anddescribed within the description of this invention, how to find otherpossible synthesis routes for compounds according to this invention. Allthese other possible synthesis routes are also part of this invention.

Having described the invention in detail, the scope of the presentinvention is not limited only to those described characteristics orembodiments. As will be apparent to persons skilled in the art,modifications, analogies, variations, derivations, homologisations andadaptations to the described invention can be made on the base ofart-known knowledge and/or, particularly, on the base of the disclosure(e.g. the explicit, implicit or inherent disclosure) of the presentinvention without departing from the spirit and scope of this inventionas defined by the scope of the appended claims.

The following examples illustrate the invention in greater detail,without restricting it. As well, further compounds according to thepresent invention, of which the preparation is explicitly not described,can be prepared in an analogous way or in a way which is known by aperson skilled in the art using customary preparation methods andprocess techniques.

Any or all of the compounds, which are mentioned in the examples asfinal compounds as well as their salts are a preferred subject of theinvention.

EXAMPLES

In the examples, m.p. stands for melting point, h for hours, d for days,min for minutes, TLC for thin layer chromatography, Rf for retentionfactor, MS for mass spectrum, M for molecular ion, ESI-MS forelectrospray ionization mass spectrometry, LC-MS for liquidchromatography coupled to mass spectrometry, Lawesson's reagent for2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide,dppf/DPPF for 1,1′-bis(diphenylphosphino)-ferrocene, Hünig's base forN,N-diisopropylethylamine. Other abbreviations have their meaningscustomary per se for the skilled person. LiChroprep-NH₂® (25-40 μm) isavailable from Merck KGaA (Darmstadt, Germany). Percentages given formolecular ion peaks in the ESI-MS refer to the intensity of each signaldue to a halogen (Br, Cl) isotope ratio.

Final Products 1.7-[2-(6-Phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine

65 mg of7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione(compound A1) are suspended in 4.3 ml of methanol containing ammonia(strength: 7.0 M) and heated at 50° C. for 90 hours. Subsequently, thereaction mixture is evaporated to dryness and purified by flashchromatography on LiChroprep-NH₂® (eluent gradient:dichloromethane/0-100 vol. % methanol), and lyophilized from 2.0 ml ofwater, 5.0 ml of dioxane to afford 29.5 mg of the title compound as anamorphous, colorless solid of m.p. 117° C. (decomp.). ESI-MS: 334.3(MH⁺). TLC: Rf=0.35 (LiChroprep-NH₂® HPTLC, methanol/water 10:1 parts byvolume).

2.7-[2-(6-{4-Cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine

The title compound is synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine(compound 1) from 90 mg of7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione(compound A2) and 5.5 ml of methanol containing ammonia (strength: 7.0M) at 50° C. for 90 hours. Purification by flash chromatography onLiChroprep-NH₂® (eluent gradient: dichloromethane/0-100 vol. % methanol)affords 43.3 mg of the title compound as an amorphous solid of m.p. 175°C. (decomp.). ESI-MS: 359.2 (MH⁺). TLC: Rf=0.33 (LiChroprep-NH₂® HPTLC,methanol/water 10:1 parts by volume).

3.7-{2-[6-(4-Methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-4,5,6,7-tetrahydro-3H-azepin-2-ylamine

The title compound is synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine(compound 1) from 98 mg of7-{2-[6-(4-methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-azepane-2-thione(compound A3) and 6.0 ml of methanol containing ammonia (strength: 7.0M) at 50° C. for 5 days. Purification by flash chromatography onLiChroprep-NH₂® (eluent: ethanol) affords 23 mg of the title compound asan amorphous, colorless solid of m.p. 306° C. ESI-MS: 364.2 (MH⁺). TLC:Rf=0.50 (LiChroprep-NH₂® HPTLC, methanol/water 10:1 parts by volume).

4.7-[2-(6-Benzofuran-2-yl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine

The title compound is synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine(compound 1) from 85 mg of7-[2-(6-benzofuran-2-yl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepane-2-thione(compound A4) and 5.0 ml of methanol containing ammonia (strength: 7.0M) at 50° C. for 70 hours. Purification by flash chromatography onLiChroprep-NH₂® (eluent gradient: ethyl acetate/0-100 vol. % 2-propanol;then: neat methanol) affords 40.4 mg of the title compound as a waxysolid. ESI-MS: 374.2 (MH⁺). TLC: Rf=0.21 (LiChroprep-NH₂® HPTLC, neatmethanol).

5.4-{2-[2-(7-Amino-3,4,5,6-tetrahydro-2H-azepin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N,N-dimethyl-benzenesulfonamide

The title compound is synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine(compound 1) from 50 mg ofN,N-dimethyl-4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide(compound A5) and 2.53 ml of methanol containing ammonia (strength: 7.0M) at 50° C. for 65 hours. Purification by flash chromatography onLiChroprep-NH₂® (eluent: dichloromethane/0-10 vol. % methanol) andlyophilisation from dioxane/water (10:1 parts by volume) afford 32 mg ofthe title compound as an amorphous, colorless solid of m.p. 195° C.(decomp.). ESI-MS: 441.2 (MH⁺). TLC: Rf=0.44 (LiChroprep-NH₂® HPTLC,methanol/water 10:1 parts by volume).

6.7-(2-{6-[4-(Azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-4,5,6,7-tetrahydro-3H-azepin-2-ylamine

The title compound is synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine(compound 1) from 92 mg of7-(2-{6-[4-(azetidine-1-sulfonylyphenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepane-2-thione(compound A6) and 4.50 ml of methanol containing ammonia (strength: 7.0M) at 50° C. for 70 hours. Purification by flash chromatography onLiChroprep-NH₂® (eluent gradient: dichloromethane/0-100 vol. % methanol)affords 56 mg of the title compound as an amorphous solid of m.p. 154°C. (decomp.). ESI-MS: 453.2 (MH⁺). TLC: Rf=0.23 (LiChroprep-NH₂® HPTLC,neat methanol).

7.7-(2-{6-[4-(4-Ethyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-4,5,6,7-tetrahydro-3H-azepin-2-ylamine

The title compound is synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine(compound 1) from 157 mg of7-(2-{6-[4-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepane-2-thione(compound A7) and 6.90 ml of methanol containing ammonia (strength: 7.0M) at 50° C. for 90 hours. Purification by flash chromatography onLiChroprep-NH₂® (eluent gradient: ethyl acetate/0-100 vol. % 2-propanol)affords 28 mg of the title compound as an amorphous solid of m.p. 199°C. ESI-MS: 528.2 (MNH₄ ⁺), 510.4 (MH⁺), TLC: Rf=0.30 (LiChroprep-NH₂®HPTLC, neat methanol).

8.4-{2-[2-(7-Amino-3,4,5,6-tetrahydro-2H-azepin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-(2-fluoro-4-methyl-phenyl)-benzenesulfonamide

The title compound is synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine(compound 1) from 100 mg ofN-(2-fluoro-4-methyl-phenyl)-4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide(compound A8) and 4.30 ml of methanol containing ammonia (strength: 7.0M) at 50° C. for 90 hours. Subsequently, the mixture is filtered withsuction. The residue is washed with 20 ml of methanol and dried underhigh vacuum to afford 61 mg of the pure title compound as an amorphous,colorless solid of m.p. 265° C. ESI-MS: 521.2 (MH⁺), TLC: Rf=0.28 (HPTLCRP-C18; acetonitrile/water 2:1 parts by volume).

9.4-{2-[2-(7-Amino-3,4,5,6-tetrahydro-2H-azepin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-o-tolyl-benzenesulfonamide

The title compound is synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine(compound 1) from 71 mg of4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-o-tolyl-benzenesulfonamide(compound A9) and 3.2 ml of methanol containing ammonia (strength: 7.0M) at 50° C. for 66 hours. Subsequently, the solution is concentrated invacuo to yield 60 mg of the pure title compound as an amorphous,colorless solid of m.p. 215° C. ESI-MS: 503.4 (MH⁺), TLC: Rf=0.25 (HPTLCRP-C18; acetonitrile/water 2:1 parts by volume).

10.4-{2-[2-(7-Amino-3,4,5,6-tetrahydro-2H-azepin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-methyl-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide

The title compound is synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine(compound 1) from 114 mg ofN-methyl-N-(tetrahydro-furan-2-ylmethyl)-4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide(compound A10) and 5.0 ml of methanol containing ammonia (strength: 7.0M) at 50° C. for 64 hours. Purification by flash chromatography on RP-C8resin (eluent: acetonitrile/water 2:1 parts by volume) andlyophilization from 1.0 ml of water and 3.0 ml of dioxane afford 14 mgof the title compound as an amorphous, colorless solid of m.p. 260° C.ESI-MS: 511.4 (MH⁺). TLC: Rf=0.17 (HPTLC RP-C18, acetonitrile/water 2:1parts by volume).

Starting Materials A1.7-[2-(6-Phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione

90 mg of7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound B1) are dissolved in 10 ml of toluene under an atmosphere ofdry nitrogen. Subsequently, 144 mg of Lawesson's reagent are added andthe solution is heated at 100° C. for 17 hours. Thereafter, the reactionmixture is evaporated to dryness to yield approximately 200 mg of crudematerial, which is purified by chromatography on basic aluminum oxide(eluent: dichloromethane) to afford 71 mg of the title compound as alight yellow, waxy solid. ESI-MS: 351.2 (MH⁺). TLC: Rf=0.53(dichloromethane/ethanol 10:1 parts by volume).

A2.7-[2-(6-{4-Cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione

120 mg of7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound B2) are suspended in 30 ml of dry dioxane under an atmosphereof nitrogen. Subsequently, 142 mg of Lawesson's reagent are added andthe solution is heated at 100° C. for 17 hours. Thereafter, the reactionmixture is evaporated to dryness to yield approximately 300 mg of crudematerial, which is purified by chromatography on flash silica gel(eluent gradient: dichloromethane/0-5 vol. % ethanol) to afford 100 mgof the title compound as a light yellow, waxy solid. ESI-MS: 376.2(MH⁺). TLC: Rf=0.38 (dichloromethane/ethanol 10:1 parts by volume).

A3.7-{2-[6-(4-Methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-azepane-2-thione

The title compound is synthesized as described for7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione(compound A2) from 120 mg of7-{2-[6-(4-methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-azepan-2-one(compound B3) and 222 mg of Lawesson's reagent. Purification bychromatography on flash silica gel (eluent gradient:dichloromethane/0-10 vol. % ethanol) affords 104 mg of the titlecompound as a light yellow, waxy solid. ESI-MS: 381.2 (MH⁺). TLC:Rf=0.64 (dichloromethane/ethanol 10:1 parts by volume).

A4.7-[2-(6-Benzofuran-2-yl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepane-2-thione

The title compound is synthesized as described for7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione(compound A2) from 100 mg of7-[2-(6-benzofuran-2-yl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound B4) and 110 mg of Lawesson's reagent. Purification bychromatography on flash silica gel (eluent gradient:dichloromethane/0-20 vol. % ethanol) yields 82 mg of the title compoundas a light yellow, waxy solid. ESI-MS: 391.2 (MH⁺). TLC: Rf=0.55(dichloromethane/ethanol 10:1 parts by volume).

A5.N,N-Dimethyl-4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide

The title compound is synthesized as described for7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione(compound A2) from 85 mg ofN,N-dimethyl-4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide(compound B5) and 82 mg of Lawesson's reagent. Purification bychromatography on flash silica gel (eluent gradient: dichloromethane/0-5vol. % ethanol) affords 56 mg of the title compound as a light yellow,waxy solid. ESI-MS: 458.3 (MH⁺). TLC: Rf=0.46 (dichloromethane/ethanol10:1 parts by volume).

A6.7-(2-{6-[4-(Azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepane-2-thione

The title compound is synthesized as described for7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione(compound A2) from 258 mg of7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one(compound B6) and 242 mg of Lawesson's reagent. Purification bychromatography on flash silica gel (eluent gradient: dichloromethane/0-5vol. % ethanol) affords 99 mg of the title compound as a beige foam.ESI-MS: 470.2 (MH⁺). TLC: Rf=0.45 (dichloromethane/ethanol 10:1 parts byvolume).

A7.7-(2-{6-[4-(4-Ethyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepane-2-thione

The title compound is analogously synthesized as described for7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione(compound A2) from 170 mg of7-(2-{6-[4-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one(compound B7) and 142 mg of Lawesson's reagent at 100° C. for 2.5 hoursin 20 ml of dioxane. Purification by chromatography on flash silica gel(eluent gradient: dichloromethane/0-10 vol. % ethanol) affords 163 mg ofthe title compound as a waxy solid. ESI-MS: 527.3 (MH⁺). TLC: Rf=0.34(dichloromethane/ethanol 10:1 parts by volume).

A8.N-(2-Fluoro-4-methyl-phenyl)-4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide

The title compound is analogously synthesized as described for7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione(compound A2) from 180 mg ofN-(2-fluoro-4-methyl-phenyl)-4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide(compound B8) and 146 mg of Lawesson's reagent at 100° C. for 3 hours in20 ml of dioxane. Purification by chromatography on flash silica gel(eluent gradient: dichloromethane/0-10 vol. % ethanol) affords 106 mg ofthe title compound as a colorless solid of m.p. 271° C. ESI-MS: 538.2(MH⁺). TLC: Rf=0.40 (dichloromethane/ethanol 10:1 parts by volume).

A9.4-{2-[2-(7-Thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-o-tolyl-benzenesulfonamide

The title compound is analogously synthesized as described for7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione(compound A2) from 88 mg of4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-o-tolyl-benzenesulfonamide(compound B9) and 77 mg of Lawesson's reagent. Purification bychromatography on LiChroprep-NH₂® (eluents: i. neat dichloromethane, ii.dichloromethane/ethanol 20:1 parts by volume) affords 78 mg of the titlecompound as a waxy solid. ESI-MS: 520.4 (MH⁺). TLC: Rf=0.44(LiChroprep-NH₂® HPTLC, dichloromethane/ethanol 10:1 parts by volume).

A10.N-Methyl-N-(tetrahydro-furan-2-ylmethyl)-4-{2-[2-(7-thioxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide

The title compound is synthesized as described for7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-thione(compound A2) from 125 mg ofN-methyl-4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide(compound B10) and 104 mg of Lawesson's reagent. Purification bychromatography on flash silica gel (eluent gradient:dichloromethane/0-10 vol. % ethanol) affords 123 mg of the titlecompound as a waxy solid. ESI-MS: 528.9 (MH⁺). TLC: Rf=0.43(dichloromethane/ethanol 10:1 parts by volume).

B1. 7-[2-(6-Phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one

100 mg of7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound C1) are dissolved in 8.0 ml of oxygen free dioxane under anatmosphere of nitrogen. Subsequently, 900 μl of aqueous sodium carbonatesolution (strength 2.0 M), 72 mg of commercially available2-phenyl-1,3,2-dioxoborinane, and 26 mg oftrans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II) are added. Thereaction mixture is stirred at 110° C. for 96 hours. Thereafter, themixture is evaporated to dryness and purified by chromatography on basicaluminum oxide (eluent: dichloromethane) to yield 95 mg of the titlecompound as a light yellow oil. ESI-MS: 335.3 (MH⁺). TLC: Rf=0.24(dichloromethane/ethanol 10:1 parts by volume).

B2.7-[2-(6-{4-Cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one

The title compound is synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound B1) from 300 mg of7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound C1), 2.67 ml of aqueous sodium carbonate solution (strength2.0 M), 306 mg of commercially available4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile, and 81 mgof trans-dichloro-bis(tricyclohexyl-phosphine)palladium(II) at 110° C.for 40 hours. Purification by chromatography on flash silica gel (eluentgradient: dichloromethane/0-10 vol. % ethanol) yields 129 mg of thetitle compound as a waxy solid. ESI-MS: 360.2 (MH⁺). TLC: Rf=0.27(dichloromethane/ethanol 10:1 parts by volume).

B3.7-{2-[6-(4-Methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-azepan-2-one

The title compound is synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound B1) from 100 mg of7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound C1), 677 μl of aqueous sodium carbonate solution (strength 2.0M), 52 mg of commercially available 4-methoxyphenylboronic acid, and 72mg of trans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II) at 110°C. for 96 hours. Purification by chromatography on flash silica gel(eluent gradient: dichloromethane/0-20 vol. % ethanol) yields 99 mg ofthe title compound as a waxy solid. ESI-MS: 365.2 (MH⁺). TLC: Rf=0.32(dichloromethane/ethanol 10:1 parts by volume).

B4.7-[2-(6-Benzofuran-2-yl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one

The title compound is synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound B1) from 300 mg of7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound C1), 2.67 ml of aqueous sodium carbonate solution (strength2.0 M), 651 mg of commercially available benzo[b]furan-2-boronic acid,and 135 mg of trans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II)at 110° C. for 6 days. Purification by chromatography on flash silicagel (eluent gradient: dichloromethane/5-20 vol. % ethanol) yields 160 mgof the title compound as an amorphous solid of m.p. 215° C. ESI-MS:375.9 (MH⁺). TLC: Rf=0.26 (dichloromethane/ethanol 10:1 parts byvolume).

B5.N,N-Dimethyl-4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-benzenesulfonamide

The title compound is analogously synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound B1) from 100 mg of7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound C1), 890 μl of aqueous sodium carbonate solution (strength 2.0M), 138 mgN,N-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide(compound C2), and 26 mg oftrans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II) at 160° C. for30 min (microwave irradiation, power 300 W). Purification bychromatography on flash silica gel (eluent gradient:dichloromethane/0-10 vol. % ethanol) yields 93 mg of the title compoundas a waxy solid. ESI-MS: 442.4 (MH⁺). TLC: Rf=0.41(dichloromethane/ethanol 10:1 parts by volume).

B6.7-(2-{6-[4-(Azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one

378 mg of 1-(4-bromo-benzenesulfonyl)-azetidine (compound C3) aredissolved in 10 ml of oxygen-free dioxane under an atmosphere of drynitrogen. Subsequently, 383 mg of bis(pinacolato)diboron, 30 mg ofPd(Cl)₂(dppf).CH₂Cl₂, 23 mg of DPPF(1,1′-bis(diphenylphosphino)-ferrocene), and 403 mg of potassium acetateare added. The reaction mixture is heated at 110° C. for 16 hours duringwhich time the former yellowish suspension becomes black (LC-MSmonitoring for boronic ester intermediate). Thereafter, 300 mg of7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound C1), 2.70 ml of aqueous sodium carbonate solution (strength2.0 M), and 66 mg oftrans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II) are added andthe reaction mixture is heated at 110° C. for 72 hours. Subsequently,the mixture is diluted with 50 ml of water and extracted three timeseach with 100 ml of dichloromethane. The organic layer is separated,dried using Na₂SO₄(solid) and concentrated in vacuo. The resulting crudematerial is purified by chromatography on flash silica gel (eluentgradient: dichloromethane/0-10 vol. % ethanol) to yield 187 mg of thetitle compound as an oil. ESI-MS: 454.2 (MH⁺). TLC: Rf=0.29(dichloromethane/ethanol 10:1 parts by volume).

B7.7-(2-{6-[4-(4-Ethyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one

The title compound is analogously synthesized as described for7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound B1) from 300 mg of7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound C1), 2.67 ml of aqueous sodium carbonate solution (strength2.0 M), 510 mg1-ethyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonyl]-piperazine(compound C4), and 131 mg oftrans-dichloro-bis(tricyclohexyl-phosphine)-palladium(II) at 110° C. for18 hours. After aqueous work-up using 200 ml of dichloromethane and 75ml of water, purification by chromatography on flash silica gel (eluentgradient: dichloromethane/5-50 vol. % ethanol) yields 175 mg of thetitle compound as a waxy solid. ESI-MS: 511.3 (MH⁺). TLC: Rf=0.30(dichloromethane/ethanol 8:1 parts by volume).

B8.N-(2-Fluoro-4-methyl-phenyl)-4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]-pyridin-6-yl}-benzenesulfonamide

The title compound is synthesized as described for7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one(compound B6) from 472 mg of4-bromo-N-(2-fluoro-4-methyl-phenyl)-benzenesulfonamide (compound C5)and 300 mg of7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound C1). Purification by chromatography on flash silica gel(eluent gradient: dichloromethane/5-20 vol. % ethanol) yields 185 mg ofthe title compound as a waxy solid. ESI-MS: 522.2 (MH⁺). TLC: Rf=0.26(dichloromethane/ethanol 10:1 parts by volume).

B9.4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-o-tolyl-benzenesulfonamide

The title compound is synthesized as described for7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one(compound B6) from 372 mg of 4-bromo-N-o-tolyl-benzenesulfonamide(compound C6) and 250 mg of7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound C1). Purification by chromatography on flash silica gel(eluent gradient: dichloromethane/0-25 vol. % ethanol) yields 138 mg ofthe title compound as a waxy solid. ESI-MS: 504.4 (MH⁺). TLC: Rf=0.18(dichloromethane/ethanol 10:1 parts by volume).

B10.N-Methyl-4-{2-[2-(7-oxo-azepan-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide

The title compound is synthesized as described for7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one(compound B6) from 458 mg of4-bromo-N-methyl-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide(compound C7) and 300 mg of7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one(compound C1). Purification by chromatography on flash silica gel(eluent gradient: dichloromethane/0-20 vol. % ethanol) yields 174 mg ofthe title compound as a waxy solid. ESI-MS: 512.4 (MH⁺). TLC: Rf=0.30(dichloromethane/ethanol 10:1 parts by volume).

C1. 7-[2-(6-Bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one

665 mg of7-[(E,Z)-2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-vinyl]-3,4,5,6-tetrahydro-azepin-2-one(compound D1) are dissolved in 50 ml of methanol. Subsequently, 91 mg ofAdam's catalyst (PtO₂) is added and the suspension is vigorously stirredunder an atmosphere of hydrogen at room temperature for 70 hours.Thereafter, the reaction mixture is evaporated to dryness, purified byflash chromatography (eluent gradient: dichloromethane/ethanol 0-10 vol.%), and lyophilized from 4.0 ml of water, 4.0 ml of dioxane, and 1.0 mlof ethanol to afford 236 mg of the title compound as an amorphous,colorless solid of m.p. 245° C. ESI-MS: 337.2/339.1 (MH⁺, 100%:98%).TLC: Rf=0.47 (dichloromethane/ethanol 10:1 parts by volume).

C2.N,N-Dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene-sulfonamide

The compound is prepared according to WO 2004009086 A1.

C3. 1-(4-Bromo-benzenesulfonyl)-azetidine

4.09 g of azetidine are dissolved in a two-phase solvent system of 200ml of dichloromethane and 130 ml of an aqueous potassium carbonatesolution (strength 4.0 M). Subsequently, a solution of 15.25 g ofcommercially available 4-bromo-benzenesulfonyl chloride in 70 ml ofdichloromethane is slowly added to the reaction mixture. Thereafter, themixture is vigorously stirred for 17 hours at room temperature. Forextraction, 200 ml of dichloromethane and 100 ml of water are added. Theorganic layer is dried using Na₂SO₄, filtered with suction, andconcentrated in vacuo to yield 15.22 g of the title compound as acolorless, amorphous solid of m.p. 145° C. ESI-MS: 276.1/278.0 (MH⁺,100%:95%). TLC: Rf=0.59 (dichloromethane/ethanol 10:1 parts by volume).

C4.1-Ethyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonyl]-piperazine

2.29 g of 1-(4-bromo-benzenesulfonyl)-4-ethyl-piperazine (compound D3),1.92 g of bis(pinacolato)diboron, 152 mg of Pd(Cl)₂(dppf).CH₂Cl₂, 114 mgof DPPF, and 2.02 g of potassium acetate are suspended in 30 ml ofdioxane. Subsequently, the reaction mixture is heated at 100° C. for 5.5hours during which time the former orange suspension becomes black.Thereafter, the reaction mixture is concentrated in vacuo. The remainingresidue is extracted three times using 150 ml of dichloromethane eachand 150 ml of water. The organic layer is dried (Na₂SO₄), filtered withsuction and evaporated to dryness to yield 3.73 g of a crude material,which is purified by flash chromatography (eluent gradient:toluene/acetone 4:1 parts by volume+5-8 vol. % methanol) to afford 2.47g of the title compound as an amorphous solid of m.p. 125° C. ESI-MS:381.2 (MH⁺). TLC: Rf=0.83 (dichloromethane/ethanol 8:1 parts by volume).

C5. 4-Bromo-N-(2-fluoro-4-methyl-phenyl)-benzenesulfonamide

The title compound is analogously synthesized as described for1-(4-bromo-benzenesulfonyl)-azetidine (compound C3) from 767 mg of4-bromo-benzenesulfonyl chloride, 451 mg of commercially available2-fluoro-4-methyl-aniline in 12.0 ml of dichloromethane and 6.0 ml ofK₂CO₃ solution to yield 727 mg of the title compound as colorless,amorphous solid of m.p. 111° C. ESI-MS: 361.2/363.3 (MNH₄ ⁺, 100%:87%).TLC: Rf=0.57 (neat dichloromethane).

C6. 4-Bromo-N-o-tolyl-benzenesulfonamide

The title compound is analogously synthesized as described for1-(4-bromo-benzenesulfonyl)-azetidine (compound C3) from 1.28 g of4-bromo-benzenesulfonyl chloride, 643 mg of commercially availableo-toluidine in 20 ml of dichloromethane and 10 ml of K₂CO₃ solution.Purification by chromatography on flash silica gel (eluent: neatdichloromethane) affords 830 mg of the title compound as colorless,amorphous solid of m.p. 114° C. GC-MS: 327.0 (MH⁺). TLC: Rf=0.58 (neatdichloromethane).

C7. 4-Bromo-N-methyl-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide

4.30 g of 4-bromo-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide(compound D2) are dissolved in 150 ml of dry tetrahydrofuran. 590 mg ofsodium hydride (strength 60 wt. % dispersion in mineral oil) are addedin portions to the solution. After 15 min, 1.67 ml of methyl iodide areslowly added and the reaction mixture is stirred at room temperature for20 hours. Subsequently, the suspension is concentrated in vacuo,extracted using 200 ml of ethyl acetate and 100 ml of half-saturatedbrine (sodium chloride solution). The organic layer is dried usingNa₂SO₄, filtered with suction, and concentrated in vacuo to yield 4.53 gof the title compound as an oil. ESI-MS: 334.2/336.0 (MH⁺, 100%:98%).TLC: Rf=0.78 (dichloromethane/ethanol 20:1 parts by volume).

D1.7-[(E,Z)-2-(6-Bromo-3H-imidazo[4,5-b]pyridin-2-yl)-vinyl]-3,4,5,6-tetrahydro-azepin-2-one

I) 503 mg of sodium hydride (strength 60 wt. % dispersion in mineraloil) are suspended in 90 ml of tetrahydrofuran under an atmosphere ofdry nitrogen. Subsequently, a suspension of 4.23 g of(6-bromo-3H-imidazo[4,5-b]pyridin-2-ylmethyl)-tributyl-phosphoniumchloride (compound I1) in 90 ml of tetrahydrofuran are added in thecourse of 5 min. Thereafter, the suspension is heated at 90° C. for 1hour.

II) 1.70 g of 7-hydroxymethyl-azepan-2-on (compound F1) are dissolved in180 ml of tetrahydrofuran under an atmosphere of dry nitrogen.Subsequently, 4.44 g of triacetoxy periodinane (Dess-Martin reagent) areadded at room temperature and stirring is continued for further 3 hours.Thereafter, the suspension is carefully neutralized using sodium hydride(strength 60 wt. % dispersion in mineral oil) and added dropwise to thereaction mixture of I) at 90° C. during 20 min. Stirring at 90° C. iscontinued for 17 hours. Subsequently, the suspension is evaporated todryness and purified by flash chromatography (eluent gradient:dichloromethane/0-10 vol. % ethanol) to afford 809 mg of the titlecompound as an oil. ESI-MS: 333.2/335.2 (MH⁺, 100%:98%). TLC: Rf=0.44(dichloromethane/ethanol 10:1 parts by volume).

Alternatively to the afore-described use of 7-oxo-azepane-2-carbaldehydein-situ, isolated 7-oxo-azepane-2-carbaldehyde (compound E1) can be usedin the Wittig reaction.

D2. 4-Bromo-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide

1.70 ml of commercially available tetrahydrofurfurylamine are dissolvedin 45 ml of dry dichloromethane. A solution of 3.83 g of4-bromo-benzenesulfonyl chloride in 20 ml of dichloromethane are slowlyadded at room temperature. Subsequently, 5.14 ml of Hünig's base areadded and stirring is continued for 1.5 hours. For extraction, thereaction mixture is diluted with 150 ml of dichloromethane and 50 ml ofwater. The organic layer is dried using Na₂SO₄, filtered with suction,and concentrated in vacuo. Purification by chromatography on flashsilica gel (eluent: dichloromethane/0-5 vol. % ethanol) affords 4.33 gof the title compound as an light yellow oil. ESI-MS: 320.3/322.1 (MH⁺,100%:98%). TLC: Rf=0.65 (dichloromethane/ethanol 20:1 parts by volume).

D3. 1-(4-Bromo-benzenesulfonyl)-4-ethyl-piperazine

The title compound is prepared according to WO 2003004472 A1.

E1. 7-Oxo-azepane-2-carbaldehyde

750 mg of 7-hydroxymethyl-azepan-2-on (compound F1) are dissolved in 85ml of dichloromethane under an atmosphere of dry nitrogen. Subsequently,2.22 g of triacetoxy periodinane (Dess-Martin reagent) are added at roomtemperature and stirring is continued for further 3 hours. Thereafter,the suspension is evaporated to dryness to yield 2.65 g of crudematerial. The crude product is purified by chromatography (eluentgradient: cyclohexane/50-100 vol. % ethyl acetate) to afford 272 mg ofthe title compound as a colorless, waxy solid. ESI-MS: 140.1 (MH⁺). TLC:Rf=0.60 (dichloromethane/ethanol 10:1 parts by volume).

F1. 7-Hydroxymethyl-azepan-2-on

3.10 g of 7-oxo-azepane-2-carboxylic acid ethyl ester (compound G1) aredissolved in 150 ml of dichloromethane under an atmosphere of drynitrogen. At room temperature, 8.45 ml of lithium boron hydride solutionin tetrahydrofuran (strength 2.0 M) are slowly added to the solution inthe course of 10 min. Thereafter, the reaction mixture is stirred for 17hours overnight at room temperature. Subsequently, the mixture is cooledin an ice bath and acidified to pH 1 using hydrochloric acid (strength3.0 M). Under stirring, the reaction mixture is allowed to warm up toroom temperature. Thereafter, potassium carbonate is carefully addedthereby re-adjusting neutral pH. The reaction mixture is filtered withsuction and the filtrate is concentrated in vacuo. Purification isachieved by flash chromatography (eluent gradient: dichloromethane/0-10vol. % ethanol) to yield 1.46 g of the title compound as colorless solidof m.p. 100° C. ESI-MS: 144.1 (MH⁺). TLC: Rf=0.47(dichloromethane/ethanol 10:1 parts by volume; iodine staining).

G1. 7-Oxo-azepane-2-carboxylic acid ethyl ester

The title compound is synthesized according to a procedure described byL. Benati et al., J. Org. Chem. 1999, 64(21), 7836-7841 using compoundH1.

H1. 1-Azido-2-oxo-cyclohexanecarboxylic acid ethyl ester

The title compound is synthesized according to procedures described byL. Benati et al., J. Org. Chem. 1999, 64(21), 7836-7841 and L. Benati etal., J. Org. Chem. 1999, 64(14), 5132-5138.

I1. (6-Bromo-3H-imidazo[4,5-b]pyridin-2-ylmethyl)-tributyl-phosphoniumchloride

4.0 g of 6-bromo-2-chloromethyl-3H-imidazo[4,5-b]pyridine (compound J1)are suspended in 16 ml of N,N-dimethylformamide and 54 ml ofacetonitrile. 4.9 ml of triphenylphosphine and 0.599 g oftetrabutylammonium iodide are added sequentially at 40° C. and themixture is heated to 90° C. for 20 h. The mixture is concentrated todryness to give the 8.94 g of the crude title compound as an oil, whichis used as obtained. MS: 412.3, 414.2 (M⁺). TLC: Rf=0.40-0.55(dichloromethane/methanol 10:1 parts by volume).

Alternatively, 4.0 g of 6-bromo-2-chloromethyl-3H-imidazo[4,5-b]pyridine(compound J1) are suspended in 17 ml of N,N-dimethylformamide and 54 mlof acetonitrile. 4.8 ml of tributylphosphine and 600 mg oftetrabutylammonium iodide are added sequentially at 40° C. Subsequently,the mixture is heated to 90° C. for 18 hours. The mixture isconcentrated to dryness to give 8.94 g of the crude title compound as anoil, which is purified by chromatography on flash silica gel (eluentgradient: dichloromethane/5-20 vol. % 2-propanol). The remaining residueis re-dissolved in 150 ml of ethyl acetate. Upon standing at roomtemperature, a precipitate of the title compound is formed, which iscollected by filtration and dried under high vacuum to yield 4.52 g of(6-bromo-3H-imidazo[4,5-b]pyridin-2-ylmethyl)-tributyl-phosphoniumchloride as an amorphous solid of m.p. 180° C. ESI-MS: 412.5, 414.4 (M⁺,100%:98%). TLC: Rf=0.45-0.55 (dichloromethane/methanol 10:1 parts byvolume).

J1. 6-Bromo-2-chloromethyl-3H-imidazo[4,5-b]pyridine

3.0 g of 5-bromo-2,3-diaminopyridine (S.-X. Cai et al., J. Med. Chem.1997, 40(22), 3679-3686) in 120 g of polyphosphoric acid are heated at160° C. for 0.5 h. The solution is cooled to 100° C. and 1.26 ml ofchloroacetonitrile are added. Thereafter, the reaction mixture is heatedto 170° C. for 22 h. After cooling, the polyphosphoric acid ishydrolysed with 81 ml of water. After reheating to 90° C., charcoal isadded under vigorous stirring. Subsequently, the suspension is filteredthrough a celite pad while still hot (70° C.). The filter cake is rinsedwith 85 ml of water. The filtrate is adjusted to pH 4 using 9.0 Maqueous sodium hydroxide solution. The precipitate is collected,suspended in 100 ml of hot methanol and filtered over celite. Thefiltrate is concentrated to dryness to afford 2.78 g of the titlecompound as a beige, amorphous solid of m.p. >325° C. MS:246.2/248.2/250.3 (MH⁺, 77%/100%/25%). TLC: Rf=0.42(dichloromethane/methanol 10:1 parts by volume).

Commercial Applicability

The compounds according to the invention have valuable pharmacologicalproperties which make them commercially utilizable. They are selectiveinhibitors of the enzyme inducible nitric oxide synthase. Nitric oxidesynthases (NO-syntases, NOSs) are enzymes that generate NO andcitrulline from the amino acid arginine. In certain pathophysiologicalsituations such as arginine depletion or tetrahydrobiopterin depletionthe generation of O₂ ⁻ from NO-synthases instead or together with NO hasbeen reported. NO is long known as a signalling molecule in most livingorganisms including mammals and humans. The most prominent action of NOis it's smooth muscle relaxing activity, which is caused on themolecular level by the activation of soluble guanylate cyclase. In thelast years a lot of other enzymes have been shown to be regulated by NOor reaction products of NO. There exist three isoforms of NO-synthaseswhich fall into two classes and differ in their physiologic functionsand molecular properties. The first class, known as constitutiveNO-synthases, comprises of the endothelial NO-synthase and the neuronalNO-synthase. Both isoenzymes are expressed constitutively in variouscell types, but are most prominent in endothelial cells of blood vesselwalls (therefore called endothelial NO-synthase, eNOS or NOS-III) and inneuronal cells (therefore called neuronal NO-synthase, nNOS or NOS-I).Activation of these two enzymes is dependent on Ca²⁺/Calmodulin which isgenerated by transient increases of the intracellular free Ca²⁺concentration. Activation of constitutive isoforms leads to transientbursts of nitric oxide resulting in nanomolar cellular or tissue NOconcentrations. The endothelial isoform is involved in the physiologicregulation of blood pressure. NO generated by the neuronal isoform seemsto have neurotransmitter function and the neuronal isoform is amongother regulatory processes involved in memory function (long termpotentiation).

In contrast to the constitutive isoforms the activation of inducibleNO-synthase (iNOS, NOS-II), the sole member of the second class, isperformed by transcriptional activation of the iNOS-promoter.Proinflammatory stimuli lead to transcription of the gene for inducibleNO-synthase, which is catalytically active without increases in theintracellular Ca²⁺-concentration. Due to the long half life of theinducible NO-synthase and the unregulated activity of the enzyme, highmicromolar concentrations of NO are generated over longer time periods.These high NO-concentrations alone or in cooperation with other reactiveradicals such as O₂ ⁻ are cytotoxic. Therefore, in situations ofmicrobial infections, iNOS is involved in cell killing by macrophagesand other immune cells during early nonspecific immune responses.

There are a number of pathophysiological situations which among othersare characterized by the high expression of inducible NO-synthase andconcomitant high NO or O₂ ⁻ concentrations. It has been shown that thesehigh NO concentrations alone or in combination with other radicalspecies lead to tissue and organ damage and are causally involved inthese pathophysiologies. As inflammation is characterized by theexpression of proinflammatory enzymes, including inducible NO-synthase,acute and chronic inflammatory processes are promising diseases for thetherapeutic application of selective inhibitors of inducibleNO-synthase. Other pathophysiologies with high NO-production frominducible NO-synthase are several forms of shock (septic, hemorrhagicand cytokine-induced). It is clear that nonselective NO-synthaseinhibitors will lead to cardiovascular and neuronal side effects due toconcomitant inhibition of constitutive NO-synthase isoforms.

It has been shown in in-vivo animal models of septic shock thatreduction of circulating plasma NO-levels by NO-scavenger or inhibitionof inducible NO-synthase restores systemic blood pressure, reduces organdamage and increases survival (deAngelo Exp. Opin. Pharmacother. 19-29,1999; Redl et al. Shock 8, Suppl. 51, 1997; Strand et al. Crit. CareMed. 26, 1490-1499, 1998). It has also been shown that increased NOproduction during septic shock contributes to cardiac depression andmyocardial dysfunction (Sun et al. J. Mol.Cell Cardiol. 30, 989-997,1998). Furthermore there are also reports showing reduced infarct sizeafter occlusion of the left anterior coronary artery in the presence ofNO-synthase inhibitors (Wang et al. Am. J. Hyperttens. 12, 174-182,1999). Considerable inducible NO-synthase activity is found in humancardiomyopathy and myocarditis, supporting the hypothesis that NOaccounts at least in part for the dilatation and impaired contractilityin these pathophysiologies (de Belder et al. Br. Heart. J. 4, 426-430,1995).

In animal models of acute or chronic inflammation, blockade of inducibleNO-synthase by isoform-selective or nonselective inhibitors or geneticknock out improves therapeutic outcome. It is reported that experimentalarthritis (Connor et al. Eur. J. Pharmacol. 273, 15-24, 1995) andosteoarthritis (Pelletier et al. Arthritis & Rheum. 41, 1275-1286,1998), experimental inflammations of the gastro-intestinal tract(Zingarelli et al. Gut 45, 199-209, 1999), experimentalglomerulonephritis (Narita et al. Lab. Invest. 72, 17-24, 1995),experimental diabetes (Corbett et al. PNAS 90, 8992-8995, 1993),LPS-induced experimental lung injury is reduced by inhibition ofinducible NO-synthase or in iNOS-knock out mice (Kristof et al. Am. J.Crit. Care. Med. 158, 1883-1889, 1998). A pathophysiological role ofinducible NO-synthase derived NO or O₂ ⁻ is also discussed in chronicinflammatory diseases such as asthma, bronchitis and COPD (chronicobstructive pulmonary disease).

Furthermore, in models of neurodegenerative diseases of the centralnervous system (CNS) such as MPTP-induced parkinsonism(MPTP=1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), amyloid peptideinduced Alzheimer's disease (Ishii et al., FASEB J. 14, 1485-1489,2000), malonate induced Huntington's disease (Connop et al.Neuropharmacol. 35, 459-465, 1996), experimental meningitis (Korytko &Boje Neuropharmacol. 35, 231-237, 1996) and experimental encephalitis(Parkinson et al. J. Mol. Med. 75, 174-186, 1997) a causal participationof NO and inducible NO-synthase has been shown.

Increased iNOS expression has been found in the brains of AIDS (acquiredimmunodeficiency syndrome) victims and it is reasonable to assume a roleof iNOS in AIDS related dementia (Bagasra et al. J. Neurovirol. 3153-167, 1997).

Other studies implicated nitric oxide as a potential mediator ofmicroglia dependent primary demyelination, a hallmark of multiplesclerosis (Parkinson et al. J. Mol. Med. 75, 174-186, 1997).

An inflammatory reaction with concomitant expression of inducibleNO-synthase also takes place during cerebral ischemia and reperfusion(ladecola et al. Stroke 27, 1373-1380, 1996). Resulting NO together withO₂ ⁻ from infiltrating neutrophils is thought to be responsible forcellular and organ damage.

Also, in models of traumatic brain injury (Mesenge et al. J. Neurotrauma13, 209-214, 1996; Wada et al. Neurosurgery 43, 1427-1436, 1998)NO-synthase inhibitors have been shown to possess protective properties.A regulatory role for inducible NO-synthase has been reported in varioustumor cell lines (Tozer & Everett Clin Oncol. 9. 357-264, 1997).

On account of their inducible NO-synthase-inhibiting properties, thecompounds according to the invention can be employed in human andveterinary medicine and therapeutics, where an excess of NO or O₂ ⁻ dueto increases in the activity of inducible NO-synthase is involved. Theycan be used without limitation for the treatment and prophylaxis of thefollowing diseases:

Acute inflammatory diseases: Septic shock, sepsis, SIRS (systemicinflammatory response syndrome), hemorrhagic shock, shock states inducedby cytokine therapy [IL-2 (interleukin-2), TNF (tumor necrosis factor)],septic and postoperative ileus, organ transplantation and transplantrejection, head trauma, acute lung injury, ARDS (acute respiratorydistress syndrome), inflammatory skin conditions such as sunburn,inflammatory eye conditions such as uveitis, glaucoma andconjunctivitis.

Chronic inflammatory diseases of peripheral organs and the CNS:gastrointestinal inflammatory diseases such as Crohn's disease,inflammatory bowel disease, ulcerative colitis, lung inflammatorydiseases such as asthma and COPD as well as allergic rhinitis, arthriticdisorders such as rheumatoid arthritis, osteoarthritis and goutyarthritis, heart disorders such as cardiomyopathy and myocarditis,atherosclerosis, neurogenic inflammation, skin diseases such aspsoriasis, dermatitis and eczema, diabetes, glomerulonephritis;dementias such as dementias of the Alzheimer's type, vascular dementia,dementia due to a general medical condition, such as AIDS, Parkinson'sdisease, Huntington's induced dementias, ALS (amyotrophic lateralsclerosis), multiple sclerosis; necrotizing vasculitides such aspolyarteritis nodosa, serum sickness, Wegener's granulomatosis,Kawasaki's syndrome; headaches such as migraine, chronic tensionheadaches, cluster and vascular headaches, post-traumatic stressdisorders; pain disorders such as neuropathic pain; myocardial andcerebral ischemia/reperfusion injury.

The compounds may also be useful in the treatment of cancers thatexpress nitric oxide synthase.

In the context of their properties, functions and usabilities mentionedherein, the compounds according to the invention are distinguished byvaluable and desirable effects related therewith, such as, for example,high efficacy, high selectivity, low toxicity, superior bioavailabilityin general (e.g. good enteral absorption, low microsomal clearance, lowserum protein binding), superior therapeutic window, absence ofsignificant side effects and further beneficial effects related withtheir therapeutic and pharmaceutical suitability.

The invention further relates to a method for the treatment of mammals,including humans, which are suffering from one of the abovementionedillnesses. The method is characterized in that a therapeutically activeand pharmacologically effective and tolerable amount of one or more ofthe compounds according to the invention is administered to the illmammal.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of illnesses,especially the illnesses mentioned.

The invention also relates to the use of the compounds according to theinvention for the production of pharmaceutical compositions which areemployed for the treatment and/or prophylaxis of the illnessesmentioned.

The invention also relates to the use of the compounds according to theinvention for the production of pharmaceutical compositions having aniNOS inhibitory activity.

The invention furthermore relates to pharmaceutical compositions for thetreatment and/or prophylaxis of the illnesses mentioned, which containone or more of the compounds according to the invention.

The invention moreover relates to pharmaceutical compositions accordingto this invention having an iNOS inhibitory activity.

The pharmaceutical compositions are prepared by processes which areknown per se and familiar to the person skilled in the art. Aspharmaceutical compositions, the compounds according to the invention(=active compounds) are either employed as such, or preferably incombination with suitable pharmaceutical auxiliaries and/or excipients,e.g. in the form of tablets, coated tablets, capsules, caplets,suppositories, patches [e.g. as TTS (transdermal therapeutic systems)],emulsions, suspensions, gels or solutions, the active compound contentadvantageously being between 0.1 and 95 wt. % and where, by theappropriate choice of the auxiliaries and/or excipients, apharmaceutical administration form (e.g. a delayed release form or anenteric form) exactly suited to the active compound and/or to thedesired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries or excipientswhich are suitable for the desired pharmaceutical formulations onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound excipients, forexample antioxidants, dispersants, emulsifiers, preservatives,solubilizers, colorants, complexing agents or permeation promoters, canbe used.

The administration of the pharmaceutical compositions according to theinvention may be performed in any of the generally accepted modes ofadministration available in the art. Illustrative examples of suitablemodes of administration include intravenous, oral, nasal, parenteral,topical, transdermal and rectal delivery. Oral and intravenous deliveryare preferred.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation in the form of an aerosol; the aerosol particles of solid,liquid or mixed composition preferably having a diameter of 0.5 to 10μm, advantageously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-drivenjet atomizers or ultrasonic atomizers, but advantageously bypropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from inhalation capsules.

Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), andautomatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

For the treatment of dermatoses, the compounds according to theinvention are in particular administered in the form of thosepharmaceutical compositions which are suitable for topical application.For the production of the pharmaceutical compositions, the compoundsaccording to the invention (=active compounds) are preferably mixed withsuitable pharmaceutical auxiliaries and further processed to givesuitable pharmaceutical formulations. Suitable pharmaceuticalformulations are, for example, powders, emulsions, suspensions, sprays,oils, ointments, fatty ointments, creams, pastes, gels or solutions.

The pharmaceutical compositions according to the invention are preparedby processes known per se. The dosage of the active compounds is carriedout in the order of magnitude customary for iNOS inhibitors. Topicalapplication forms (such as ointments) for the treatment of dermatosesthus contain the active compounds in a concentration of, for example,0.1-99 wt. %. The dose for administration by inhalation is customarilybetween 0.1 and 10 mg per day. The customary dose in the case ofsystemic therapy (p.o.) is between 0.3 and 30 mg/kg per day, (i. v.) isbetween 0.3 and 30 mg/kg/h.

Biological Investigations Measurement of Inducible NO-Synthase Activity

The assay is performed in 96-well microtiter F-plates (Greiner,Frickenhausen, FRG) in a total volume of 100 μl in the presence of 100nM calmodulin, 226 μM CaCl₂, 477 μM MgCl₂, 5 μMflavin-adenine-dinucleotide (FAD), 5 μM flavin mononucleotide (FMN), 0.1mM nicotinamide adenine dinucleotide phosphate (NADPH), 7 mMglutathione, 10 μM tetrahydrobiopterine (BH4) and 100 mM4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES) pH 7.2.Arginine concentrations are 0.1 μM for enzyme inhibition experiments.150000 dpm of [³H]arginine are added to the assay mixture. Enzymereaction is started by the addition of 4 μg of a crude cytosolicfraction containing human inducible NO-synthase and the reaction mixtureis incubated for 45 to 60 min at 37° C. Enzyme reaction is stopped byadding 10 μl of 2M 2-morpholinoethane sulfonic acid buffer (MES-buffer)pH 5.0. 50 μl of the incubation mixture are transferred into a MADP N65filtration microtiter plate (Millipore, Eschborn, FRG) containingalready 50 μl of AG-50W-X8 cation exchange resin (Biorad, München, FRG).The resin in the Na loaded form is pre-equilibrated in water and 70 μl(corresponding to 50 μl dry beads) are pipetted under heavy stirringwith a 8 channel pipette into the filtration plate. After pipetting 50μl of the enzyme reaction mixture onto the filtration plates, the platesare placed on a filtration manifold (Porvair, Shepperton, UK) and theflow through is collected in Pico scintillation plates (Packard,Meriden, Conn.). The resin in the filtration plates is washed with 75 μlof water (1×50 μl and 1×25 μl) which is also collected in the same plateas the sample. The total flow through of 125 μl is mixed with 175 μl ofMicroscint-40 scintillation cocktail (Packard) and the scintillationplate is sealed with TopSeal P-foil (Packard). Scintillation plates arecounted in a szintillation counter.

For the measurement of inducible NO-synthase-inhibiting potencies ofcompounds according to the invention increasing concentrations ofinhibitors are included into the incubation mixture. IC₅₀ values arecalculated from the percent inhibition at given concentrations bynonlinear least square fitting.

Representative inhibitory values which are determined for compoundsaccording to the invention follow from the following table A, in whichthe compound numbers correspond to the example numbers.

Measurement of Inducible NO-Synthase Activity in the Presence of 20%Human Plasma Serum

The assay determining the human plasma serum binding of compoundsaccording to the invention was performed essentially as the enzymaticactivity assay described above. Human plasma serum 20% (v/v) was addedinto the reaction volume. Human serum was obtained after coagulation andsedimentation of drawn donor blood. After centrifugation (two times 3500rpm, 30 min) the plasma serum was dialyzed in phosphate buffered saline(PBS) for 18 h using dialysis cassettes with a molecular weight cuttoffof 3500 Dalton (Slide-a-Lyzer 3.5 K, Pierce, Rockford Ill.) in order toreduce the L-arginine concentration that is interfering with theradioactive activity assay. The buffer was refreshed 5 times duringdialysis. The serum was aliquoted and frozen at −20° C. until use.Inhibitory potency of the compounds according to the invention wasdetermined as described above.

Representative values for compounds according to the invention are givenin the following table A, in which the compound numbers correspond tothe example numbers.

TABLE A Inhibition of iNOS activity [measured as −logIC₅₀ (mol/l)]−logIC₅₀ compound −logIC₅₀ 20% human serum 1 6.77 6.00 2 6.65 6.40 36.60 5.80 4 6.64 6.02 5 6.64 6.03 6 6.52 6.22 7 6.33 8 6.23 9 6.40 106.21

1-15. (canceled)
 16. A method of treating an acute inflammatory diseasein a patient comprising administering to said patient a compound offormula I

in which A is 1-4C-alkylene or 3-7C-cycloalkylene, R1 is phenyl, R2—and/or R3-substituted phenyl, Har1, or R4— and/or R5-substituted Har1,R11 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, in which R2 iscyano, halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, aminocarbonyl, mono-or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino,trifluoromethyl, hydroxyl, 1-4C-alkylsulfonylamino, phenylsulfonylamino,phenyl-1-4C-alkoxy, or —SO₂—N(R21)R22, in which R21 is hydrogen,1-4C-alkyl, 3-7C-cycloalkyl, phenyl-1-4C-alkyl, Har2-1-4C-alkyl,hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl, pyridyl, or R211-and/or R212-substituted phenyl, in which Har2 is pyridyl, thienyl, furylor tetrahydrofuryl, R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono-or di-1-4C-alkylamino, R212 is 1-4C-alkyl or halogen, R22 is hydrogen,1-4C-alkyl, hydroxy-2-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl, or R21 and R22together and with inclusion of the nitrogen atom, to which they arebonded, form a heterocyclic ring Het1, in which Het1 is a fullysaturated or partially unsaturated mono- or fused bicyclic ring or ringsystem made up of a first constituent being a 3- to 7-memberedmonocyclic fully saturated non-aromatic heterocyclic ring B, whichheterocyclic ring B comprises one to three heteroatoms independentlyselected from the group consisting of nitrogen, oxygen and sulfur, andwhich heterocyclic ring B is optionally substituted by one or two oxogroups, and, optionally, fused to said first constituent, a secondconstituent being a benzene ring, and which ring Het1 is optionallysubstituted by R23 on a ring carbon atom, and/or which ring Het1 isoptionally substituted by R24 on a further ring carbon atom, and/orwhich ring Het1 is optionally substituted by an ethylenedioxy group on aring carbon atom, and/or which ring Het1 is optionally substituted byR25 on a ring nitrogen atom, in which R23 is 1-4C-alkyl, 1-4C-alkoxy orphenylcarbonyl, R24 is 1-4C-alkyl or 1-4C-alkoxy, R25 is 1-4C-alkyl,phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkoxy-2-4C-alkyl, mono- ordi-1-4C-alkylamino-2-4C-alkyl, phenyl, pyrimidyl, pyridyl, formyl,3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, or R251- and/or R252-substitutedphenyl, in which R251 is halogen, cyano or 1-4C-alkyl, R252 is halogenor 1-4C-alkyl, R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl,1-4C-alkoxy, or completely or predominantly fluorine-substituted1-4C-alkoxy, Har1 is bonded to the parent molecular group via a ringcarbon atom, and is a monocyclic or fused bicyclic 5- to 10-memberedunsaturated or partially saturated heteroaryl radical comprising one tothree heteroatoms, each of which is selected from the group consistingof nitrogen, oxygen and sulfur, R4 is 1-4C-alkyl, halogen, cyano,trifluoromethyl, phenyl, mono- or di-1-4C-alkylamino, formyl,1-4C-alkylcarbonyl, carboxyl or 1-4C-alkoxy, R5 is 1-4C-alkyl orhalogen, or a pharmaceutically acceptable enantiomer, salt, or salt ofan enantiomer thereof, wherein the acute inflammatory disease isselected from the group consisting of acute lung injury, acuterespiratory distress syndrome (ARDS), uveitis, glaucoma andconjunctivitis.
 17. The method according to claim 16 in which A is1-4C-alkylene or 3-7C-cycloalkylene, R1 is phenyl, R2— and/orR3-substituted phenyl, Har1, or R4— and/or R5-substituted Har1, R11 ishydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, in which R2 is cyano,halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino,trifluoromethyl, hydroxyl, 1-4C-alkylsulfonylamino, phenylsulfonylamino,phenyl-1-4C-alkoxy, or —SO₂—N(R21)R22, in which R21 is hydrogen,1-4C-alkyl, 3-7C-cycloalkyl, phenyl-1-4C-alkyl, Har2-1-4C-alkyl,hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl, pyridyl, or R211-and/or R212-substituted phenyl, in which Har2 is pyridyl, thienyl orfuryl, R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono- ordi-1-4C-alkylamino, R212 is 1-4C-alkyl or halogen, R22 is hydrogen,1-4C-alkyl, hydroxy-2-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl, or R21 and R22together and with inclusion of the nitrogen atom, to which they arebonded, form a heterocyclic ring Het1, in which Het1 is a fullysaturated or partially unsaturated mono- or fused bicyclic ring or ringsystem made up of a first constituent being a 3- to 7-memberedmonocyclic fully saturated non-aromatic heterocyclic ring B, whichheterocyclic ring B comprises one to three heteroatoms independentlyselected from the group consisting of nitrogen, oxygen and sulfur, andwhich heterocyclic ring B is optionally substituted by one or two oxogroups, and, optionally, fused to said first constituent, a secondconstituent being a benzene ring, and which ring Het1 is optionallysubstituted by R23 on a ring carbon atom, and/or which ring Het1 isoptionally substituted by R24 on a further ring carbon atom, and/orwhich ring Het1 is optionally substituted by an ethylenedioxy group on aring carbon atom, and/or which ring Het1 is optionally substituted byR25 on a ring nitrogen atom, in which R23 is 1-4C-alkyl, 1-4C-alkoxy orphenylcarbonyl, R24 is 1-4C-alkyl or 1-4C-alkoxy, R25 is 1-4C-alkyl,phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkoxy-2-4C-alkyl, mono- ordi-1-4C-alkylamino-2-4C-alkyl, phenyl, pyrimidyl, pyridyl, formyl,3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, or R251- and/or R252-substitutedphenyl, in which R251 is halogen, cyano or 1-4C-alkyl, R252 is halogenor 1-4C-alkyl, R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl,1-4C-alkoxy, or completely or predominantly fluorine-substituted1-4C-alkoxy, Har1 is bonded to the parent molecular group via a ringcarbon atom, and is a monocyclic or fused bicyclic 5- to 10-memberedunsaturated or partially saturated heteroaryl radical comprising one tothree heteroatoms, each of which is selected from the group consistingof nitrogen, oxygen and sulfur, R4 is 1-4C-alkyl, halogen, cyano,trifluoromethyl, phenyl, mono- or di-1-4C-alkylamino, formyl,1-4C-alkylcarbonyl, carboxyl or 1-4C-alkoxy, R5 is 1-4C-alkyl orhalogen, or a pharmaceutically acceptable enantiomer, salt, or salt ofan enantiomer thereof.
 18. The method according to claim 16 in which Ais ethylene or cyclopropylene, R1 is bonded to the 6-position of theimidazopyridine scaffold, and is phenyl, R2- and/or R3-substitutedphenyl, or Hart R11 is hydrogen, in which R2 is cyano, halogen,carboxyl, 1-4C-alkyl, 1-4C-alkoxy, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino,trifluoromethyl, hydroxyl, 1-4C-alkylsulfonylamino, phenylsulfonylamino,phenyl-1-4C-alkoxy, or —SO₂—N(R21)R22, in which R21 is hydrogen,1-4C-alkyl, 3-7C-cycloalkyl, phenyl-1-4C-alkyl, Har2-1-4C-alkyl,hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl, pyridyl, or R211-and/or R212-substituted phenyl, in which Har2 is pyridyl, thienyl orfuryl, R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono- ordi-1-4C-alkylamino, R212 is 1-4C-alkyl or halogen, R22 is hydrogen,hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or 1-4C-alkyl, or R21 and R22together and with inclusion of the nitrogen atom, to which they arebonded, form a heterocyclic ring Het1, in which Het1 is piperidinyl,pyrrolidinyl, azetidinyl, morpholinyl, thiomorpholinyl,S-oxo-thiomorpholinyl or S,S-dioxo-thiomorpholinyl, indolinyl,isoindolinyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, homopiperazinyl,4N—(R25)-piperazinyl, 4N—(R25)-homopiperazinyl, 2-oxopyrrolidinyl,2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl,2,5-dioxoimidazolidinyl, 2,6-dioxopiperidinyl, 2-oxopiperazinyl,2,6-dioxopiperazinyl, 5-oxo-1,4-diazepanyl,3-(R25)-imidazolidin-2-one-yl, 3-(R25)-imidazolidin-2,5-dione-yl,4-(R25)-piperazine-2-one-yl, 4-(R25)-piperazine-2,6-dione-yl or4-(R25)-1,4-diazepan-5-one-yl, in which R25 is 1-4C-alkyl,phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkoxy-2-4C-alkyl, mono- ordi-1-4C-alkylamino-2-4C-alkyl, phenyl, pyrimidyl, pyridyl, formyl,3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, or R251- and/or R252-substitutedphenyl, in which R251 is halogen, cyano or 1-4C-alkyl, R252 is halogenor 1-4C-alkyl, R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl,1-4C-alkoxy, or completely or predominantly fluorine-substituted1-4C-alkoxy, Har1 is bonded to the parent molecular group via a ringcarbon atom, and is pyridyl, thienyl, furanyl, indolyl, benzothienyl,benzofuranyl, benzoxazolyl, benzothiazolyl, quinolyl or isoquinolyl, ora pharmaceutically acceptable enantiomer, salt, or salt of an enantiomerthereof.
 19. The method according to claim 16 in which A is ethylene, R1is bonded to the 6-position of the imidazopyridine scaffold, and isphenyl, or R2— and/or R3-substituted phenyl, R11 is hydrogen, in whichR2 is cyano, halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, aminocarbonyl,mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino,trifluoromethyl, hydroxyl, 1-4C-alkylsulfonylamino, phenylsulfonylamino,or phenyl-1-4C-alkoxy, R3 is hydrogen, 1-4C-alkyl, halogen,trifluoromethyl, 1-4C-alkoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, or a pharmaceutically acceptableenantiomer, salt, or salt of an enantiomer thereof.
 20. The methodaccording to claim 16 in which A is ethylene, R1 is bonded to the6-position of the imidazopyridine scaffold, and is R2- and/orR3-substituted phenyl or Har1, R11 is hydrogen, in which R2 is—SO₂—N(R21)R22, in which R21 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,phenyl-1-4C-alkyl, Har2-1-4C-alkyl, hydroxy-2-4C-alkyl,1-4C-alkoxy-2-4C-alkyl, phenyl, pyridyl, or R211- and/orR212-substituted phenyl, in which Har2 is pyridyl, thienyl or furyl,R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono- ordi-1-4C-alkylamino, R212 is 1-4C-alkyl or halogen, R22 is hydrogen,hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or 1-4C-alkyl, or R21 and R22together and with inclusion of the nitrogen atom, to which they arebonded, form a heterocyclic ring Het1, in which Het1 is piperidinyl,pyrrolidinyl, azetidinyl, morpholinyl, thiomorpholinyl,S-oxo-thiomorpholinyl or S,S-dioxo-thiomorpholinyl, indolinyl,isoindolinyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, homopiperazinyl,4N—(R25)-piperazinyl, 4N—(R25)-homopiperazinyl, 2-oxopyrrolidinyl,2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl,2,5-dioxoimidazolidinyl, 2,6-dioxopiperidinyl, 2-oxopiperazinyl,2,6-dioxopiperazinyl, 5-oxo-1,4-diazepanyl,3-(R25)-imidazolidin-2-one-yl, 3-(R25)-imidazolidin-2,5-dione-yl,4-(R25)-piperazine-2-one-yl, 4-(R25)-piperazine-2,6-dione-yl or4-(R25)-1,4-diazepan-5-one-yl, in which R25 is 1-4C-alkyl,phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkoxy-2-4C-alkyl, mono- ordi-1-4C-alkylamino-2-4C-alkyl, phenyl, pyrimidyl, pyridyl, formyl,3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, or R251- and/or R252-substitutedphenyl, in which R251 is halogen, cyano or 1-4C-alkyl, R252 is halogenor 1-4C-alkyl, R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl,1-4C-alkoxy, or completely or predominantly fluorine-substituted1-4C-alkoxy, Har1 is bonded to the parent molecular group via a ringcarbon atom, and is pyridyl, thienyl, furanyl, indolyl, benzothienyl,benzofuranyl, benzoxazolyl, benzothiazolyl, quinolyl or isoquinolyl, ora pharmaceutically acceptable enantiomer, salt, or salt of an enantiomerthereof.
 21. The method according to claim 16 in which A is1-4C-alkylene, R1 is phenyl, R2-substituted phenyl or Hart R11 ishydrogen, in which R2 is cyano, 1-4C-alkoxy or —SO₂—N(R21)R22, in whichR21 is hydrogen, 1-4C-alkyl, Har2-1-4C-alkyl, phenyl or R211- and/orR212-substituted phenyl, in which Har2 is furyl or tetrahydrofuranyl,R211 is 1-4C-alkyl or halogen, R212 is 1-4C-alkyl or halogen, R22 ishydrogen or 1-4C-alkyl, or R21 and R22 together and with inclusion ofthe nitrogen atom, to which they are bonded, form a heterocyclic ringHet1, in which Het1 is a 3- to 7-membered monocyclic fully saturatednon-aromatic heterocyclic ring B, which heterocyclic ring B comprisesone to three heteroatoms independently selected from the groupconsisting of nitrogen, oxygen and sulfur, and which ring Het1 isoptionally substituted by R23 on a ring carbon atom, and/or which ringHet1 is optionally substituted by R25 on a ring nitrogen atom, in whichR23 is 1-4C-alkyl, R25 is 1-4C-alkyl, Har1 is bonded to the parentmolecular group via a ring carbon atom, and is a monocyclic or fusedbicyclic 5- to 10-membered unsaturated heteroaryl radical comprising oneto three heteroatoms, each of which is selected from the groupconsisting of nitrogen, oxygen and sulfur, or a pharmaceuticallyacceptable enantiomer, salt, or salt of an enantiomer thereof.
 22. Themethod according to claim 16 in which A is ethylene, R1 is phenyl,R2-substituted phenyl or Hart R11 is hydrogen, in which R2 is cyano,1-4C-alkoxy or —SO₂—N(R21)R22, in which R21 is hydrogen, 1-4C-alkyl,Har2-1-4C-alkyl or R211- and/or R212-substituted phenyl, in which Har2is tetrahydrofuranyl, R211 is 1-4C-alkyl or halogen, R212 is 1-4C-alkyl,R22 is hydrogen or 1-4C-alkyl, or R21 and R22 together and withinclusion of the nitrogen atom, to which they are bonded, form aheterocyclic ring Het1, in which Het1 is a 4- to 6-membered monocyclicfully saturated non-aromatic heterocyclic ring B, which heterocyclicring B comprises one to three nitrogen atoms, and which ring Het1 isoptionally substituted by R25 on a ring nitrogen atom, in which R25 is1-4C-alkyl, Har1 is bonded to the parent molecular group via a ringcarbon atom, and is a fused bicyclic 9-membered unsaturated heteroarylradical comprising one oxygen atom, or a pharmaceutically acceptableenantiomer, salt, or salt of an enantiomer thereof.
 23. The methodaccording to claim 16 in which A is ethylene, R1 is phenyl,R2-substituted phenyl or Hart R11 is hydrogen, in which R2 is cyano,1-4C-alkoxy or —SO₂—N(R21)R22, in which R21 is hydrogen, 1-4C-alkyl,Har2-1-4C-alkyl or R211- and/or R212-substituted phenyl, in which Har2is tetrahydrofuranyl, R211 is 1-4C-alkyl or halogen, R212 is 1-4C-alkyl,R22 is hydrogen or 1-4C-alkyl, or R21 and R22 together and withinclusion of the nitrogen atom, to which they are bonded, form aheterocyclic ring Het1, in which Het1 is an azetidinyl or piperazinylring, which ring Het1 is optionally substituted by R25 on a ringnitrogen atom, in which R25 is 1-4C-alkyl, Har1 is bonded to the parentmolecular group via a ring carbon atom, and is a benzofuranyl ring, or apharmaceutically acceptable enantiomer, salt, or salt of an enantiomerthereof.
 24. The method according to claim 16, wherein the compound isselected from the group consisting of7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine,7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine,7-{2-[6-(4-methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-4,5,6,7-tetrahydro-3H-azepin-2-ylamine,7-[2-(6-benzofuran-2-yl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine,4-{2-[2-(7-amino-3,4,5,6-tetrahydro-2H-azepin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N,N-dimethyl-benzenesulfonamide,7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-4,5,6,7-tetrahydro-3H-azepin-2-ylamine,7-(2-{6-[4-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-4,5,6,7-tetrahydro-3H-azepin-2-ylamine,4-{2-[2-(7-amino-3,4,5,6-tetrahydro-2H-azepin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-(2-fluoro-4-methyl-phenyl)-benzenesulfonamide,4-{2-[2-(7-amino-3,4,5,6-tetrahydro-2H-azepin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-o-tolyl-benzenesulfonamideand4-{2-[2-(7-amino-3,4,5,6-tetrahydro-2H-azepin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-methyl-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide.25. A method of treating a chronic inflammatory disease of a peripheralorgan or central nervous system in a patient comprising administering tosaid patient a compound of formula I

in which A is 1-4C-alkylene or 3-7C-cycloalkylene, R1 is phenyl, R2-and/or R3-substituted phenyl, Har1, or R4- and/or R5-substituted Har1,R11 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, in which R2 iscyano, halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, aminocarbonyl, mono-or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino,trifluoromethyl, hydroxyl, 1-4C-alkylsulfonylamino, phenylsulfonylamino,phenyl-1-4C-alkoxy, or —SO₂—N(R21)R22, in which R21 is hydrogen,1-4C-alkyl, 3-7C-cycloalkyl, phenyl-1-4C-alkyl, Har2-1-4C-alkyl,hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl, pyridyl, or R211-and/or R212-substituted phenyl, in which Har2 is pyridyl, thienyl, furylor tetrahydrofuryl, R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono-or di-1-4C-alkylamino, R212 is 1-4C-alkyl or halogen, R22 is hydrogen,1-4C-alkyl, hydroxy-2-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl, or R21 and R22together and with inclusion of the nitrogen atom, to which they arebonded, form a heterocyclic ring Het1, in which Het1 is a fullysaturated or partially unsaturated mono- or fused bicyclic ring or ringsystem made up of a first constituent being a 3- to 7-memberedmonocyclic fully saturated non-aromatic heterocyclic ring B, whichheterocyclic ring B comprises one to three heteroatoms independentlyselected from the group consisting of nitrogen, oxygen and sulfur, andwhich heterocyclic ring B is optionally substituted by one or two oxogroups, and, optionally, fused to said first constituent, a secondconstituent being a benzene ring, and which ring Het1 is optionallysubstituted by R23 on a ring carbon atom, and/or which ring Het1 isoptionally substituted by R24 on a further ring carbon atom, and/orwhich ring Het1 is optionally substituted by an ethylenedioxy group on aring carbon atom, and/or which ring Het1 is optionally substituted byR25 on a ring nitrogen atom, in which R23 is 1-4C-alkyl, 1-4C-alkoxy orphenylcarbonyl, R24 is 1-4C-alkyl or 1-4C-alkoxy, R25 is 1-4C-alkyl,phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkoxy-2-4C-alkyl, mono- ordi-1-4C-alkylamino-2-4C-alkyl, phenyl, pyrimidyl, pyridyl, formyl,3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, or R251- and/or R252-substitutedphenyl, in which R251 is halogen, cyano or 1-4C-alkyl, R252 is halogenor 1-4C-alkyl, R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl,1-4C-alkoxy, or completely or predominantly fluorine-substituted1-4C-alkoxy, Har1 is bonded to the parent molecular group via a ringcarbon atom, and is a monocyclic or fused bicyclic 5- to 10-memberedunsaturated or partially saturated heteroaryl radical comprising one tothree heteroatoms, each of which is selected from the group consistingof nitrogen, oxygen and sulfur, R4 is 1-4C-alkyl, halogen, cyano,trifluoromethyl, phenyl, mono- or di-1-4C-alkylamino, formyl,1-4C-alkylcarbonyl, carboxyl or 1-4C-alkoxy, R5 is 1-4C-alkyl orhalogen, or a pharmaceutically acceptable enantiomer, salt, or salt ofan enantiomer thereof, wherein the chronic inflammatory disease of aperipheral organ or central nervous system is selected from the groupconsisting of COPD, asthma, allergic rhinitis, rheumatoid arthritis,osteoarthritis, neuropathic pain, psoriasis, dermatitis, Crohn's diseaseand ulcerative colitis.
 26. The method according to claim 25 in which Ais 1-4C-alkylene or 3-7C-cycloalkylene, R1 is phenyl, R2- and/orR3-substituted phenyl, Har1, or R4- and/or R5-substituted Har1, R11 ishydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, in which R2 is cyano,halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino,trifluoromethyl, hydroxyl, 1-4C-alkylsulfonylamino, phenylsulfonylamino,phenyl-1-4C-alkoxy, or —SO₂—N(R21)R22, in which R21 is hydrogen,1-4C-alkyl, 3-7C-cycloalkyl, phenyl-1-4C-alkyl, Har2-1-4C-alkyl,hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl, pyridyl, or R211-and/or R212-substituted phenyl, in which Har2 is pyridyl, thienyl orfuryl, R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono- ordi-1-4C-alkylamino, R212 is 1-4C-alkyl or halogen, R22 is hydrogen,1-4C-alkyl, hydroxy-2-4C-alkyl or 1-4C-alkoxy-2-4C-alkyl, or R21 and R22together and with inclusion of the nitrogen atom, to which they arebonded, form a heterocyclic ring Het1, in which Het1 is a fullysaturated or partially unsaturated mono- or fused bicyclic ring or ringsystem made up of a first constituent being a 3- to 7-memberedmonocyclic fully saturated non-aromatic heterocyclic ring B, whichheterocyclic ring B comprises one to three heteroatoms independentlyselected from the group consisting of nitrogen, oxygen and sulfur, andwhich heterocyclic ring B is optionally substituted by one or two oxogroups, and, optionally, fused to said first constituent, a secondconstituent being a benzene ring, and which ring Het1 is optionallysubstituted by R23 on a ring carbon atom, and/or which ring Het1 isoptionally substituted by R24 on a further ring carbon atom, and/orwhich ring Het1 is optionally substituted by an ethylenedioxy group on aring carbon atom, and/or which ring Het1 is optionally substituted byR25 on a ring nitrogen atom, in which R23 is 1-4C-alkyl, 1-4C-alkoxy orphenylcarbonyl, R24 is 1-4C-alkyl or 1-4C-alkoxy, R25 is 1-4C-alkyl,phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkoxy-2-4C-alkyl, mono- ordi-1-4C-alkylamino-2-4C-alkyl, phenyl, pyrimidyl, pyridyl, formyl,3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, or R251- and/or R252-substitutedphenyl, in which R251 is halogen, cyano or 1-4C-alkyl, R252 is halogenor 1-4C-alkyl, R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl,1-4C-alkoxy, or completely or predominantly fluorine-substituted1-4C-alkoxy, Har1 is bonded to the parent molecular group via a ringcarbon atom, and is a monocyclic or fused bicyclic 5- to 10-memberedunsaturated or partially saturated heteroaryl radical comprising one tothree heteroatoms, each of which is selected from the group consistingof nitrogen, oxygen and sulfur, R4 is 1-4C-alkyl, halogen, cyano,trifluoromethyl, phenyl, mono- or di-1-4C-alkylamino, formyl,1-4C-alkylcarbonyl, carboxyl or 1-4C-alkoxy, R5 is 1-4C-alkyl orhalogen, or a pharmaceutically acceptable enantiomer, salt, or salt ofan enantiomer thereof.
 27. The method according to claim 25 in which Ais ethylene or cyclopropylene, R1 is bonded to the 6-position of theimidazopyridine scaffold, and is phenyl, R2- and/or R3-substitutedphenyl, or Hart R11 is hydrogen, in which R2 is cyano, halogen,carboxyl, 1-4C-alkyl, 1-4C-alkoxy, aminocarbonyl, mono- ordi-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino,trifluoromethyl, hydroxyl, 1-4C-alkylsulfonylamino, phenylsulfonylamino,phenyl-1-4C-alkoxy, or —SO₂—N(R21)R22, in which R21 is hydrogen,1-4C-alkyl, 3-7C-cycloalkyl, phenyl-1-4C-alkyl, Har2-1-4C-alkyl,hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl, pyridyl, or R211-and/or R212-substituted phenyl, in which Har2 is pyridyl, thienyl orfuryl, R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono- ordi-1-4C-alkylamino, R212 is 1-4C-alkyl or halogen, R22 is hydrogen,hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or 1-4C-alkyl, or R21 and R22together and with inclusion of the nitrogen atom, to which they arebonded, form a heterocyclic ring Het1, in which Het1 is piperidinyl,pyrrolidinyl, azetidinyl, morpholinyl, thiomorpholinyl,S-oxo-thiomorpholinyl or S,S-dioxo-thiomorpholinyl, indolinyl,isoindolinyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, homopiperazinyl,4N—(R25)-piperazinyl, 4N—(R25)-homopiperazinyl, 2-oxopyrrolidinyl,2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl,2,5-dioxoimidazolidinyl, 2,6-dioxopiperidinyl, 2-oxopiperazinyl,2,6-dioxopiperazinyl, 5-oxo-1,4-diazepanyl,3-(R25)-imidazolidin-2-one-yl, 3-(R25)-imidazolidin-2,5-dione-yl,4-(R25)-piperazine-2-one-yl, 4-(R25)-piperazine-2,6-dione-yl or4-(R25)-1,4-diazepan-5-one-yl, in which R25 is 1-4C-alkyl,phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkoxy-2-4C-alkyl, mono- ordi-1-4C-alkylamino-2-4C-alkyl, phenyl, pyrimidyl, pyridyl, formyl,3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, or R251- and/or R252-substitutedphenyl, in which R251 is halogen, cyano or 1-4C-alkyl, R252 is halogenor 1-4C-alkyl, R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl,1-4C-alkoxy, or completely or predominantly fluorine-substituted1-4C-alkoxy, Har1 is bonded to the parent molecular group via a ringcarbon atom, and is pyridyl, thienyl, furanyl, indolyl, benzothienyl,benzofuranyl, benzoxazolyl, benzothiazolyl, quinolyl or isoquinolyl, ora pharmaceutically acceptable enantiomer, salt, or salt of an enantiomerthereof.
 28. The method according to claim 25 in which A is ethylene, R1is bonded to the 6-position of the imidazopyridine scaffold, and isphenyl, or R2- and/or R3-substituted phenyl, R11 is hydrogen, in whichR2 is cyano, halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, aminocarbonyl,mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino,1-4C-alkoxycarbonyl, amino, mono- or di-1-4C-alkylamino,trifluoromethyl, hydroxyl, 1-4C-alkylsulfonylamino, phenylsulfonylamino,or phenyl-1-4C-alkoxy, R3 is hydrogen, 1-4C-alkyl, halogen,trifluoromethyl, 1-4C-alkoxy, or completely or predominantlyfluorine-substituted 1-4C-alkoxy, or a pharmaceutically acceptableenantiomer, salt, or salt of an enantiomer thereof.
 29. The methodaccording to claim 25 in which A is ethylene, R1 is bonded to the6-position of the imidazopyridine scaffold, and is R2- and/orR3-substituted phenyl or Har1, R11 is hydrogen, in which R2 is—SO₂—N(R21)R22, in which R21 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl,phenyl-1-4C-alkyl, Har2-1-4C-alkyl, hydroxy-2-4C-alkyl,1-4C-alkoxy-2-4C-alkyl, phenyl, pyridyl, or R211- and/orR212-substituted phenyl, in which Har2 is pyridyl, thienyl or furyl,R211 is 1-4C-alkyl, halogen, 1-4C-alkoxy, or mono- ordi-1-4C-alkylamino, R212 is 1-4C-alkyl or halogen, R22 is hydrogen,hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or 1-4C-alkyl, or R21 and R22together and with inclusion of the nitrogen atom, to which they arebonded, form a heterocyclic ring Het1, in which Het1 is piperidinyl,pyrrolidinyl, azetidinyl, morpholinyl, thiomorpholinyl,S-oxo-thiomorpholinyl or S,S-dioxo-thiomorpholinyl, indolinyl,isoindolinyl, 1,2,3,4-tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, homopiperazinyl,4N—(R25)-piperazinyl, 4N—(R25)-homopiperazinyl, 2-oxopyrrolidinyl,2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl,2,5-dioxoimidazolidinyl, 2,6-dioxopiperidinyl, 2-oxopiperazinyl,2,6-dioxopiperazinyl, 5-oxo-1,4-diazepanyl,3-(R25)-imidazolidin-2-one-yl, 3-(R25)-imidazolidin-2,5-dione-yl,4-(R25)-piperazine-2-one-yl, 4-(R25)-piperazine-2,6-dione-yl or4-(R25)-1,4-diazepan-5-one-yl, in which R25 is 1-4C-alkyl,phenyl-1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkoxy-2-4C-alkyl, mono- ordi-1-4C-alkylamino-2-4C-alkyl, phenyl, pyrimidyl, pyridyl, formyl,3-7C-cycloalkyl, 3-7C-cycloalkylmethyl, or R251- and/or R252-substitutedphenyl, in which R251 is halogen, cyano or 1-4C-alkyl, R252 is halogenor 1-4C-alkyl, R3 is hydrogen, 1-4C-alkyl, halogen, trifluoromethyl,1-4C-alkoxy, or completely or predominantly fluorine-substituted1-4C-alkoxy, Har1 is bonded to the parent molecular group via a ringcarbon atom, and is pyridyl, thienyl, furanyl, indolyl, benzothienyl,benzofuranyl, benzoxazolyl, benzothiazolyl, quinolyl or isoquinolyl, ora pharmaceutically acceptable enantiomer, salt, or salt of an enantiomerthereof.
 30. The method according to claim 25 in which A is1-4C-alkylene, R1 is phenyl, R2-substituted phenyl or Hart R11 ishydrogen, in which R2 is cyano, 1-4C-alkoxy or —SO₂—N(R21)R22, in whichR21 is hydrogen, 1-4C-alkyl, Har2-1-4C-alkyl, phenyl or R211- and/orR212-substituted phenyl, in which Har2 is furyl or tetrahydrofuranyl,R211 is 1-4C-alkyl or halogen, R212 is 1-4C-alkyl or halogen, R22 ishydrogen or 1-4C-alkyl, or R21 and R22 together and with inclusion ofthe nitrogen atom, to which they are bonded, form a heterocyclic ringHet1, in which Het1 is a 3- to 7-membered monocyclic fully saturatednon-aromatic heterocyclic ring B, which heterocyclic ring B comprisesone to three heteroatoms independently selected from the groupconsisting of nitrogen, oxygen and sulfur, and which ring Het1 isoptionally substituted by R23 on a ring carbon atom, and/or which ringHet1 is optionally substituted by R25 on a ring nitrogen atom, in whichR23 is 1-4C-alkyl, R25 is 1-4C-alkyl, Har1 is bonded to the parentmolecular group via a ring carbon atom, and is a monocyclic or fusedbicyclic 5- to 10-membered unsaturated heteroaryl radical comprising oneto three heteroatoms, each of which is selected from the groupconsisting of nitrogen, oxygen and sulfur, or a pharmaceuticallyacceptable enantiomer, salt, or salt of an enantiomer thereof.
 31. Themethod according to claim 25 in which A is ethylene, R1 is phenyl,R2-substituted phenyl or Hart R11 is hydrogen, in which R2 is cyano,1-4C-alkoxy or —SO₂—N(R21)R22, in which R21 is hydrogen, 1-4C-alkyl,Har2-1-4C-alkyl or R211- and/or R212-substituted phenyl, in which Har2is tetrahydrofuranyl, R211 is 1-4C-alkyl or halogen, R212 is 1-4C-alkyl,R22 is hydrogen or 1-4C-alkyl, or R21 and R22 together and withinclusion of the nitrogen atom, to which they are bonded, form aheterocyclic ring Het1, in which Het1 is a 4- to 6-membered monocyclicfully saturated non-aromatic heterocyclic ring B, which heterocyclicring B comprises one to three nitrogen atoms, and which ring Het1 isoptionally substituted by R25 on a ring nitrogen atom, in which R25 is1-4C-alkyl, Har1 is bonded to the parent molecular group via a ringcarbon atom, and is a fused bicyclic 9-membered unsaturated heteroarylradical comprising one oxygen atom, or a pharmaceutically acceptableenantiomer, salt, or salt of an enantiomer thereof.
 32. The methodaccording to claim 25 in which A is ethylene, R1 is phenyl,R2-substituted phenyl or Hart R11 is hydrogen, in which R2 is cyano,1-4C-alkoxy or —SO₂—N(R21)R22, in which R21 is hydrogen, 1-4C-alkyl,Har2-1-4C-alkyl or R211- and/or R212-substituted phenyl, in which Har2is tetrahydrofuranyl, R211 is 1-4C-alkyl or halogen, R212 is 1-4C-alkyl,R22 is hydrogen or 1-4C-alkyl, or R21 and R22 together and withinclusion of the nitrogen atom, to which they are bonded, form aheterocyclic ring Het1, in which Het1 is an azetidinyl or piperazinylring, which ring Het1 is optionally substituted by R25 on a ringnitrogen atom, in which R25 is 1-4C-alkyl, Har1 is bonded to the parentmolecular group via a ring carbon atom, and is a benzofuranyl ring, or apharmaceutically acceptable enantiomer, salt, or salt of an enantiomerthereof.
 33. The method according to claim 25, wherein the compound isselected from the group consisting of7-[2-(6-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine,7-[2-(6-{4-cyano-phen-1-yl}-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine,7-{2-[6-(4-methoxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-4,5,6,7-tetrahydro-3H-azepin-2-ylamine,7-[2-(6-benzofuran-2-yl-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-4,5,6,7-tetrahydro-3H-azepin-2-ylamine,4-{2-[2-(7-amino-3,4,5,6-tetrahydro-2H-azepin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N,N-dimethyl-benzenesulfonamide,7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-4,5,6,7-tetrahydro-3H-azepin-2-ylamine,7-(2-{6-[4-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-4,5,6,7-tetrahydro-3H-azepin-2-ylamine,4-{2-[2-(7-amino-3,4,5,6-tetrahydro-2H-azepin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-(2-fluoro-4-methyl-phenyl)-benzenesulfonamide,4-{2-[2-(7-amino-3,4,5,6-tetrahydro-2H-azepin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-o-tolyl-benzenesulfonamideand4-{2-[2-(7-amino-3,4,5,6-tetrahydro-2H-azepin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N-methyl-N-(tetrahydro-furan-2-ylmethyl)-benzenesulfonamide.